Associations of empirically derived dietary patterns and cognitive performance in older men: Results of the Osteoporotic Fractures in Men (MrOS) study.

OBJECTIVE: The aim of this study was to examine associations between empirically derived dietary pattern scores and cognition, as well as risk of cognitive decline, over an average of 4.6 (± 0.3) years in older men. MATERIALS AND METHODS: This analysis was conducted as part of the Osteoporotic Fractures in Men (MrOS) prospective cohort study. Diet was assessed at Visit 1 (3/2000-4/2002) by food frequency questionnaire, and dietary patterns (Western and Prudent) were derived by factor analysis. The analytic cohort comprised 4231 community-dwelling American men who were aged 65 years or more. Cognitive function was assessed with the Modified Mini-Mental State exam (3MS) and the Trails B test at Visit 1 and at Visit 2 (3/2005-5/2006). Associations between dietary pattern score and cognition and risk of cognitive decline were estimated using mixed effects regression models. Model 1 was adjusted for age, clinic site and total energy intake (TEI). Model 2 was further adjusted for calcium and vitamin D supplement use, body mass index (BMI), physical activity, smoking, diabetes and hypertension (Western diet group) and education, calcium and vitamin D supplement use, depression, BMI, physical activity, smoking and stroke (Prudent diet group). RESULTS: Adherence to the Western dietary pattern was associated with higher 3MS scores and shorter Trails B test time at Visit 1 in Model 2. Adherence to the Prudent dietary pattern was associated with higher 3MS scores in Model 1 but not Model 2. There were no independent associations between dietary pattern scores and risk of cognitive decline 4.6 (± 0.3) years later at Visit 2. CONCLUSION: The results do not support a robust protective effect of the Prudent dietary pattern on cognition in the MrOS cohort. Associations between the Western dietary pattern and better cognitive scores should be interpreted with caution. Further research is needed to understand the complex interactions between dietary patterns and cognition in older men.

Predictive value of sarcopenia components for all-cause mortality: findings from population-based cohorts.

BACKGROUND: Low grip strength and gait speed are associated with mortality. However, investigation of the additional mortality risk explained by these measures, over and above other factors, is limited. AIM: We examined whether grip strength and gait speed improve discriminative capacity for mortality over and above more readily obtainable clinical risk factors. METHODS: Participants from the Health, Aging and Body Composition Study, Osteoporotic Fractures in Men Study, and the Hertfordshire Cohort Study were analysed. Appendicular lean mass (ALM) was ascertained using DXA; muscle strength by grip dynamometry; and usual gait speed over 2.4-6 m. Verified deaths were recorded. Associations between sarcopenia components and mortality were examined using Cox regression with cohort as a random effect; discriminative capacity was assessed using Harrell's Concordance Index (C-index). RESULTS: Mean (SD) age of participants (n = 8362) was 73.8(5.1) years; 5231(62.6%) died during a median follow-up time of 13.3 years. Grip strength (hazard ratio (95% CI) per SD decrease: 1.14 (1.10,1.19)) and gait speed (1.21 (1.17,1.26)), but not ALM index (1.01 (0.95,1.06)), were associated with mortality in mutually-adjusted models after accounting for age, sex, BMI, smoking status, alcohol consumption, physical activity, ethnicity, education, history of fractures and falls, femoral neck bone mineral density (BMD), self-rated health, cognitive function and number of comorbidities. However, a model containing only age and sex as exposures gave a C-index (95% CI) of 0.65(0.64,0.66), which only increased to 0.67(0.67,0.68) after inclusion of grip strength and gait speed. CONCLUSIONS: Grip strength and gait speed may generate only modest adjunctive risk information for mortality compared with other more readily obtainable risk factors.

The Women's Health Initiative Randomized Trials and Clinical Practice: A Review.

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.

Balancing fracture risk versus risk of mortality before fracture among women aged 80 years or older.

BACKGROUND: Most fractures occur in women aged ≥80 years but competing mortality unrelated to fracture may limit the benefit of osteoporosis drug therapy for some women in late life. Our primary aim was to develop separate prediction models for non-spine fracture (NSF) and mortality before fracture to identify subsets of women with varying fracture versus mortality risks. METHODS: Separate prediction models were developed for NSF and mortality before NSF for 4895 women aged ≥80 years enrolled in the Study of Osteoporotic Fractures (SOF) or the Health Aging and Body Composition (HABC) study. Proportional hazards models modified to account for competing mortality were used to identify candidate risk factors for each outcome. Predictors associated with NSF or mortality (p < 0.2) were included in separate competing risk models to estimate the cumulative incidence of NSF and mortality before NSF during 5 years of follow-up. This process was repeated to develop separate prediction models for hip fracture and mortality before hip fracture. RESULTS: Significant predictors of NSF (race, total hip BMD, grip strength, prior fracture, falls, and use of selective serotonin reuptake inhibitors, benzodiazepines, or oral/transdermal estrogen) differed from predictors of mortality before NSF (age, walking speed, multimorbidity, weight change, shrinking, smoking, self-rated health, dementia, and use of warfarin). Within nine subsets of women defined by tertiles of risk, 5-year outcomes varied from 28% NSF and 8% mortality in the high-risk NSF/low-risk mortality subset, to 9% NSF and 22% mortality in the low-risk NSF/high-risk mortality subset. Similar results were seen for predictors of hip fracture and mortality before hip fracture. CONCLUSION: Considerable variation in 5-year competing mortality risk is present among women in late life with similar 5-year NSF risk. Both fracture risk and life expectancy should inform shared clinical decision-making regarding initiation or continuation of osteoporosis drug therapy for women aged ≥80 years.

Bone Mineral Density During and After Lactation: A Comparison of African American and Caucasian Women.

During lactation, changes in maternal calcium metabolism are necessary to provide adequate calcium for newborn skeletal development. The calcium in milk is derived from the maternal skeleton through a process thought to be mediated by the actions of parathyroid hormone-related protein (PTHrP) in combination with decreased circulating estrogen concentrations. After weaning, bone lost during lactation is rapidly regained. Most studies of bone metabolism in lactating women have been performed in Caucasian subjects. There are well-documented differences between African American (AA) and Caucasian (C) bone metabolism, including higher bone mineral density (BMD), lower risk of fracture, lower 25-hydroxyvitamin D (25(OH) D), and higher PTH in AA compared to C. In this prospective paired cohort study, BMD and markers of bone turnover were compared in self-identified AA and C mothers during lactation and after weaning. BMD decreased in both AA and C women during lactation, with similar decreases at the lumbar spine (LS) and greater bone loss in the C group at the femoral neck (FN) and total hip (TH), demonstrating that AA are not resistant to PTHrP during lactation. BMD recovery compared to the 2 week postpartum baseline was observed 6 months after weaning, though the C group did not have complete recovery at the FN. Increases in markers of bone formation and resorption during lactation were similar in AA and C. C-terminal telopeptide (CTX) decreased to 30% below post-pregnancy baseline in both groups 6 months after weaning, while procollagen type 1 N-terminal (P1NP) returned to baseline in the AA group and fell to below baseline in the C group. Further investigation is required to determine impacts on long term bone health for women who do not fully recover BMD before a subsequent pregnancy.

Self-Reported Sleep Disturbances over the Menopausal Transition and Fracture Risk: The Study of Women's Health Across the Nation.

Sleep disturbances are common and may impact fracture risk directly by influencing bone turnover or indirectly through shared risk factors or mediators. To investigate the association between self-reported sleep disturbances across the menopausal transition (MT) and fractures, we prospectively studied 3101 women enrolled in the Study of Women's Health Across the Nation (SWAN). At each of 14 study visits spaced approximately 18 months apart, a standardized validated scale ascertained trouble falling asleep, waking up several times during the night, and waking up earlier than planned. Two time-varying exposures were modeled: presence of any of the three disturbances at least three times per week and waking up several times during the night at least three times per week. Base models adjusted for fixed (race/ethnicity, study site) and time-varying characteristics (age, body mass index, and MT stage). Fully adjusted models also included time-varying bone beneficial and detrimental medications, smoking, alcohol, physical activity, diabetes, depression and sleep medications, and depressive symptoms. Women who experienced a fracture were more likely to report a greater frequency of having trouble falling asleep, waking up several times, and/or waking up earlier: 35% versus 30% at baseline, p = 0.02. In the base models, women who had any of the three sleep disturbances at least three times per week had a higher risk of any fracture, odds ratio (OR) = 1.23 (95% confidence intervals, 1.02, 1.48) and nontraumatic fracture, OR = 1.36 (1.03, 1.80). These associations were largely attenuated to nonsignificance in the fully adjusted model. Sensitivity analyses limiting our sample to 2315 SWAN women enrolled in the bone mineral density (BMD) centers yielded similar results. Additional adjustment for femoral neck BMD had no effect on our results. In conclusion, self-reported sleep disturbances were associated with an increased risk of fractures, but these associations likely reflect shared risk factors or factors in the causal pathway. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Prediabetes and Fracture Risk Among Midlife Women in the Study of Women's Health Across the Nation.

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.

Recent sarcopenia definitions-prevalence, agreement and mortality associations among men: Findings from population-based cohorts.

BACKGROUND: The 2019 European Working Group on Sarcopenia in Older People (EWGSOP2) and the Sarcopenia Definitions and Outcomes Consortium (SDOC) have recently proposed sarcopenia definitions. However, comparisons of the performance of these approaches in terms of thresholds employed, concordance in individuals and prediction of important health-related outcomes such as death are limited. We addressed this in a large multinational assembly of cohort studies that included information on lean mass, muscle strength, physical performance and health outcomes. METHODS: White men from the Health Aging and Body Composition (Health ABC) Study, Osteoporotic Fractures in Men (MrOS) Study cohorts (Sweden, USA), the Hertfordshire Cohort Study (HCS) and the Sarcopenia and Physical impairment with advancing Age (SarcoPhAge) Study were analysed. Appendicular lean mass (ALM) was ascertained using DXA; muscle strength by grip dynamometry; and usual gait speed over courses of 2.4-6 m. Deaths were recorded and verified. Definitions of sarcopenia were as follows: EWGSOP2 (grip strength <27 kg and ALM index <7.0 kg/m2 ), SDOC (grip strength <35.5 kg and gait speed <0.8 m/s) and Modified SDOC (grip strength <35.5 kg and gait speed <1.0 m/s). Cohen's kappa statistic was used to assess agreement between original definitions (EWGSOP2 and SDOC). Presence versus absence of sarcopenia according to each definition in relation to mortality risk was examined using Cox regression with adjustment for age and weight; estimates were combined across cohorts using random-effects meta-analysis. RESULTS: Mean (SD) age of participants (n = 9170) was 74.3 (4.9) years; 5929 participants died during a mean (SD) follow-up of 12.1 (5.5) years. The proportion with sarcopenia according to each definition was EWGSOP2 (1.1%), SDOC (1.7%) and Modified SDOC (5.3%). Agreement was weak between EWGSOP2 and SDOC (κ = 0.17). Pooled hazard ratios (95% CI) for mortality for presence versus absence of each definition were EWGSOP2 [1.76 (1.42, 2.18), I2 : 0.0%]; SDOC [2.75 (2.28, 3.31), I2 : 0.0%]; and Modified SDOC [1.93 (1.54, 2.41), I2 : 58.3%]. CONCLUSIONS: There was low prevalence and poor agreement among recent sarcopenia definitions in community-dwelling cohorts of older white men. All indices of sarcopenia were associated with mortality. The strong relationship between sarcopenia and mortality, regardless of the definition, illustrates that identification of appropriate management and lifecourse intervention strategies for this condition is of paramount importance.

Follicle-stimulating hormone is associated with low bone mass in postmenopausal women.

We evaluated the influence of two endogenous hormones on bone health in older women. Higher FSH was associated with bone disease, especially in lower estradiol environments. FSH attenuated the relationship between estradiol and bone. This may provide a mechanism through which future clinical research intervenes on bone loss. INTRODUCTION/PURPOSE: Despite preclinical evidence for an inverse association of follicle-stimulating hormone (FSH) and bone mineral density (BMD), no large epidemiologic studies have evaluated the separate and joint influences of FSH and estradiol on bone in postmenopausal women. METHODS: In a cross-sectional study of 675 postmenopausal women, we evaluated associations of serum FSH and dual X-ray absorptiometry (DXA)-classified areal BMD as well as low bone mass or osteoporosis (T-score < - 1.0) of the femoral neck and total hip. We stratified this analysis by serum estradiol (cut at the median). We tested whether FSH mediates the association of estradiol and BMD using the Sobel test. RESULTS: In linear regression models, there was a significant inverse association of serum FSH with both femoral neck and total hip BMD (both p < 0.01) when adjusted for age, hormone therapy (HT) use, and diabetes. In fully adjusted logistic regression models, women in the highest FSH tertile had higher odds of low bone mass/osteoporosis at the femoral neck (OR = 2.98; 95% CI = 1.86-4.77) and at the total hip (OR = 1.74; 95% CI = 1.06-2.84) compared to those in the lowest FSH tertile. We report evidence of effect modification by estradiol in stratified models and an interaction term. FSH met all criteria of a mediator, including an estimated 70% attenuation of the estradiol-BMD relationship (Sobel p value < 0.001). CONCLUSIONS: FSH is associated with higher odds of having low bone mass/osteoporosis even after accounting for HT use. FSH is a mediator of the relationship between estradiol and BMD in healthy postmenopausal women. Larger, prospective studies of FSH concentrations and bone health are needed.

Factors associated with poor sleep quality in midlife Singaporean women: The Integrated Women's Health program (IWHP).

Objective: To examine factors associated with poor sleep quality in community-dwelling midlife women. Methods: Healthy women (aged 45-69 years) of Chinese, Malay and Indian ethnicities attending well-women clinics at the National University Hospital, Singapore, completed the Pittsburgh Sleep Quality Index (PSQI). A PQSI score >5 denoted poor sleep quality. The women filled out validated questionnaires covering menopausal and genito-urinary symptoms, and mental health. Physical performance was measured. Bone mineral density and visceral adiposity were assessed by dual energy X-ray absorptiometry. Binary logistic regression analyses assessed independent factors for poor sleep. Results: Poor sleep quality was reported in 38.2% of women (n = 1094, mean age: 56.4 ± 6.2 years). Indian women had higher sleep disturbance scores than Chinese women (mean ± SD: 1.33 ± 0.58 vs 1.17 ± 0.49). Malays experienced more daytime dysfunction (0.54 ± 0.60 vs 0.33 ± 0.55) and had a higher overall PSQI score (6.00 ± 3.31 vs 5.02 ± 2.97) than the Chinese. A low education level (aOR: 1.76, 95% CI: 1.01-3.05), feelings of irritability (2.67, 1.56-4.60) and vaginal dryness (1.62, 1.03-2.54) were associated with poor sleep quality in the adjusted multivariable model. Women with moderate to severe disability were ∼3 times (2.99, 1.20-7.44) more likely to experience less than ideal sleep quality, while urinary incontinence (1.53, 1.08-2.17) and breast cancer history (2.77, 1.36-5.64) were also associates of poor sleep quality. Conclusion: Self-reports of education level, irritability, vaginal dryness, disability, urinary incontinence, and breast cancer history were independently related to poor sleep. Ethnic differences suggest the need for targeted interventions among the ethnic groups.

Long-term pelvic fracture and overall mortality risk after pelvic cancer and pelvic radiation.

BACKGROUND: The association of pelvic radiation with pelvic fracture risk has not been examined in prospective cohort settings with comprehensive fracture risk assessment, cancer-free comparison populations, and long-term follow-up. Our objective is to better characterize pelvic fracture and overall mortality risks in postmenopausal women participating in the Women's Health Initiative. METHODS: A total of 135 743 Women's Health Initiative participants aged 50 to 79 years enrolled from 40 US clinical centers from 1993 to 1998 who had entry Fracture Risk Assessment Tool scores were eligible. Outcomes included pelvic cancer diagnosis, pelvic fracture occurrence, and mortality. Cox proportional hazards regression models were used to examine associations of pelvic cancer and pelvic radiation with pelvic fracture and mortality risk. RESULTS: After 17.7 years (median) follow-up, 4451 pelvic cancers, 10 139 pelvic fractures, and 33 040 deaths occurred. In multivariable analyses, women with incident pelvic cancer, compared with women who remained pelvic cancer free, had higher pelvic fracture risk (hazard ratio [HR] = 1.26, 95% confidence interval [CI] = 1.11 to 1.43) and higher overall mortality risk (HR = 2.91, 95% CI = 2.77 to 3.05). Women with pelvic cancer treated with pelvic radiation, compared with women with pelvic cancer not treated with pelvic radiation, had higher pelvic fracture risk (HR = 1.98, 95% CI = 1.41 to 2.78) and higher overall mortality after pelvic cancer (HR = 1.32, 95% CI = 1.15 to 1.52). CONCLUSIONS: Postmenopausal women with pelvic cancer, especially those receiving pelvic radiation, are at higher pelvic fracture risk and higher overall mortality risk. As therapeutic advances have reduced cancer mortality, attention to and interventions for pelvic fracture prevention may be important in pelvic cancer survivors.

Circulating IL-10 is associated with reduced risk of prostate cancer in a prospective cohort of elderly men: the MrOS Study.

PURPOSE: Prostate cancer (PCa) is the most commonly diagnosed cancer in men, resulting in a large cancer burden given a relatively higher 5-year survival rate of patients after cancer diagnosis. The underlying etiology of prostate cancer is not well understood. Chronic inflammation plays a significant role in carcinogenesis overall and may be involved in the development of PCa, but immune-related biomarker studies in prostate cancer are limited. METHODS: The associations of serum concentrations of cytokines, systemic immune biomarkers, with risk of PCa were assessed in a randomly selected sub-cohort (n = 798, mean age = 73 years) of the Osteoporotic Fractures in Men (MrOS) study, a prospective cohort of older men. At baseline, we measured serum interleukin (IL)-6, C-reactive protein (CRP), tumor necrosis factor alpha (TNFα), soluble receptors (SR) of IL-6 (IL-6SR) and TNF (TNFαSR1 and TNFαSR2), and IL-10. The risk of PCa was calculated for higher tertile levels of measured individual cytokines relative to the lowest tertile using Cox proportional hazards regression models. RESULTS: After an average 6 years of follow-up, 59 men developed incident PCa. Men in the middle or highest tertile of IL-10 had a statistically significant 50% lower risk of PCa compared to the lowest tertile (hazard ratio = 0.50, 95% confidence interval = 0.30-0.84). There was no significant association between any of the other cytokines measured and PCa risk. CONCLUSION: IL-10, an anti-inflammatory cytokine, was associated with lower risk of PCa. Further research of IL-10 and inflammation in relation to PCa development is warranted.

Relation Between Dietary Protein Intake and Gut Microbiome Composition in Community-Dwelling Older Men: Findings from the Osteoporotic Fractures in Men Study (MrOS).

BACKGROUND: Little is known about the association of specific nutrients, especially proteins, on age-related gut dysbiosis. OBJECTIVES: To determine the associations between the quantity and sources (vegetable and animal) of dietary protein intake and gut microbiome composition in community-dwelling older men. METHODS: We performed a cross-sectional analysis on 775 older men from the Osteoporotic Fractures in Men Study (MrOS) (age 84.2 ± 4.0 y) with available dietary information and stool samples at visit 4 (2014-2016). Protein intake was estimated from a brief FFQ and adjusted to total energy intake. The gut microbiome composition was determined by 16S (v4) sequencing (processed by DADA2 and SILVA). A total of 11,534 amplicon sequence variants (ASVs) were identified and assigned to 21 phyla with dominance of Firmicutes (45%) and Bacteroidetes (43%). We performed α-diversity, ß-diversity, and taxa abundance (by Analysis of Compositions of Microbiomes with Bias Correction [ANCOM-BC]) to determine the associations between protein intake and the gut microbiome. RESULTS: Median protein intake was 0.7 g/(kg body weight · d). Participants with higher energy-adjusted protein intakes had higher Shannon and Chao1 α-diversity indices (P < 0.05). For ß-diversity analysis, participants with higher protein intakes had a different center in weighted and unweighted UniFrac Principal Co-ordinates Analysis (PCoA) compared with those with lower intake (P < 0.05), adjusted for age, race, education, clinical center, batch number, fiber and energy intake, weight, height, and medications. Similarly, higher protein consumptions from either animal or vegetable sources were associated with higher gut microbiome diversity. Several genus-level ASVs, including Christensenellaceae, Veillonella, Haemophilus, and Klebsiella were more abundant in participants with higher protein intakes, whereas Clostridiales bacterium DTU089 and Desulfovibrio were more abundant in participants with lower protein intake (Bonferroni corrected P < 0.05). CONCLUSIONS: We observed significant associations between protein intake and gut microbiome diversity in community-living older men. Further studies are needed to elucidate the mediation role of the gut microbiome on the relation between protein intake and health outcomes in older adults.

Longitudinal associations of insulin resistance with change in bone mineral density in midlife women.

BACKGROUNDThe effects of insulin resistance on bone mineral density (BMD) are unclear.METHODSIn Study of Women's Health Across the Nation (SWAN) participants, we used multivariable regression to test average insulin resistance (homeostatic model assessment of insulin resistance, HOMA-IR) and rate of change in insulin resistance as predictors of rate of change in lumbar spine (LS) and femoral neck (FN) BMD in 3 stages: premenopause (n = 861), menopause transition (MT) (n = 571), and postmenopause (n = 693). Models controlled for age, average BW, change in BW, cigarette use, race and ethnicity, and study site.RESULTSThe relation between HOMA-IR and BMD decline was biphasic. When average log2HOMA-IR was less than 1.5, greater HOMA-IR was associated with slower BMD decline; i.e., each doubling of average HOMA-IR in premenopause was associated with a 0.0032 (P = 0.01, LS) and 0.0041 (P = 0.004, FN) g/cm2 per year slower BMD loss. When greater than or equal to 1.5, average log2HOMA-IR was not associated with BMD change. In women in whom HOMA-IR decreased in premenopause, the association between the HOMA-IR change rate and BMD change rate was positive; i.e, slower HOMA-IR decline was associated with slower BMD loss. In women in whom insulin resistance increased in premenopause, the association was negative; i.e, faster HOMA-IR rise was associated with faster BMD decline. Associations of average HOMA-IR and HOMA-IR change rate with BMD change rate were similar in postmenopause, but weaker during the MT.CONCLUSIONWhen it decreases, insulin resistance is associated with BMD preservation; when it increases, insulin resistance is associated with BMD loss.FUNDINGThe SWAN has grant support from the NIH of the Department of Health and Human Services (DHHS) through the NIH National Institute on Aging (NIA), National Institute of Nursing Research (NINR), and Office of Research on Women's Health (ORWH) (grants U01NR004061, U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, U01AG012495, and U19AG063720).

The Associations between Upper and Lower Body Muscle Strength and Diabetes among Midlife Women.

We hypothesized that a combined index of upper and lower body muscle strength would be more strongly associated with diabetes than either measure alone. Women recruited into the Integrated Women's Health Program had their handgrip strength (HGS) measured using a dynamometer and underwent a timed 5-repetition chair stand (RCS) test. HGS < 18 kg and RCS performance ≥ 12 s assessed upper and lower body strength, respectively, both individually and combined in a muscle strength index (MSI). Diabetes was defined as physician-diagnosed, use of anti-diabetic medication, or fasting blood glucose ≥ 7.0 mmol/L. Binary logistic regression examined the associations between muscle strength and diabetes. Of 1170 midlife women, 12.1% had diabetes. A low HGS was independently associated with diabetes (aOR: 1.59, 95% CI: 1.03, 2.44). Prolonged RCS was also associated with diabetes (aOR: 1.59, 95% CI: 1.09, 2.30), but this was not independent of visceral adiposity and muscle mass. A poor MSI had higher odds of diabetes (aOR: 2.37, 95% CI: 1.40, 4.03), independent of age, ethnicity, education level, menopausal status, smoking, alcohol consumption, physical activity, height, visceral adiposity, and muscle mass. The combination of both upper and lower body muscle strength into a composite MSI was more strongly associated with diabetes than either weak HGS or prolonged RCS alone in midlife women.

Cumulative Endogenous Estrogen Exposure Is Associated With Postmenopausal Fracture Risk: The Women's Health Initiative Study.

We aimed to evaluate the relationship between cumulative endogenous estrogen exposure and fracture risk in 150,682 postmenopausal women (aged 50 to 79 years at baseline) who participated in the Women's Health Initiative. We hypothesized that characteristics indicating lower cumulative endogenous estrogen exposure would be associated with increased fracture risk. We determined ages at menarche and menopause as well as history of irregular menses from baseline questionnaires and calculated years of endogenous estrogen exposure from ages at menarche and menopause. Incident clinical fractures were self-reported over an average 16.7 years of follow-up. We used multivariable proportional hazards models to assess the associations between the estrogen-related variables and incidence of any clinical fracture. In fully adjusted models, those with the fewest years of endogenous estrogen exposure (<30) had an 11% higher risk of developing central body fractures and a 9% higher risk of lower extremity fractures than women with 36 to 40 years of endogenous estrogen exposure (the reference category). In contrast, women with the most years of endogenous estrogen exposure (more than 45 years) had a 9% lower risk of lower extremity fractures than the reference category. Women with irregular (not monthly) menstrual cycles were 7% to 8% more likely to experience lower extremity fractures than women with regular monthly cycles. Our findings support the hypothesis that characteristics signifying lower cumulative endogenous estrogen exposure are associated with higher fracture risk. © 2022 American Society for Bone and Mineral Research (ASBMR).

Skeletal and extraskeletal disorders of biomineralization.

The physiological process of biomineralization is complex and deviation from it leads to a variety of diseases. Progress in the past 10 years has enhanced understanding of the genetic, molecular and cellular pathophysiology underlying these disorders; sometimes, this knowledge has both facilitated restoration of health and clarified the very nature of biomineralization as it occurs in humans. In this Review, we consider the principal regulators of mineralization and crystallization, and how dysregulation of these processes can lead to human disease. The knowledge acquired to date and gaps still to be filled are highlighted. The disorders of mineralization discussed comprise a broad spectrum of conditions that encompass bone disorders associated with alterations of mineral quantity and quality, as well as disorders of extraskeletal mineralization (hyperphosphataemic familial tumoural calcinosis). Included are disorders of alkaline phosphatase (hypophosphatasia) and phosphate homeostasis (X-linked hypophosphataemic rickets, fluorosis, rickets and osteomalacia). Furthermore, crystallopathies are covered as well as arterial and renal calcification. This Review discusses the current knowledge of biomineralization derived from basic and clinical research and points to future studies that will lead to new therapeutic approaches for biomineralization disorders.

Prediabetes and insulin resistance are associated with lower trabecular bone score (TBS): cross-sectional results from the Study of Women's Health Across the Nation TBS Study.

In pre- and early perimenopausal women, prediabetes (with blood glucose ≥ 110 mg/dL) and greater insulin resistance are associated with worse trabecular bone quality (as assessed by trabecular bone score). PURPOSE: Diabetes mellitus (DM) is associated with lower trabecular bone score (TBS) and fracture; less certain is whether the precursor states of prediabetes and increased insulin resistance are also related to adverse bone outcomes. We examined, in women who do not have DM, the associations of glycemic status (prediabetes vs. normal) and insulin resistance with TBS. METHODS: This was a cross-sectional analysis of baseline data collected from 42- to 52-year-old, pre- and perimenopausal participants in the Study of Women's Health Across the Nation (SWAN) TBS Study. Women with prediabetes were categorized as having either high prediabetes if their fasting glucose was between 110 and 125 mg/dL or low prediabetes if their fasting glucose was between 100 and 109 mg/dL. Normoglycemia was defined as a fasting glucose below 100 mg/dL. RESULTS: In multivariable linear regression, adjusted for age, race/ethnicity, menopause transition stage, cigarette use, calcium and vitamin D supplementation, lumbar spine bone mineral density, and study site, women with high prediabetes had 0.21 (p < 0.0001) standard deviations (SD) lower TBS than those with normoglycemia. Low prediabetes was not associated with lower TBS. When HOMA-IR levels were ≥ 1.62, each doubling of HOMA-IR was associated with a 0.11 SD decrement in TBS (p = 0.0001). CONCLUSION: Similar to diabetics, high prediabetics have lower TBS than normoglycemic individuals. Women with greater insulin resistance have lower TBS even in the absence of DM. Future studies should examine the associations of high prediabetes and insulin resistance with incident fracture.

Validation of a Semiautomatic Image Analysis Software for the Quantification of Musculoskeletal Tissues.

Accurate quantification of bone, muscle, and their components is still an unmet need in the musculoskeletal field. Current methods to quantify tissue volumes in 3D images are expensive, labor-intensive, and time-consuming; thus, a reliable, valid, and quick application is highly needed. Tissue Compass is a standalone software for semiautomatic segmentation and automatic quantification of musculoskeletal organs. To validate the software, cross-sectional micro-CT scans images of rat femur (n = 19), and CT images of hip and abdomen (n = 100) from the Osteoporotic Fractures in Men (MrOS) Study were used to quantify bone, hematopoietic marrow (HBM), and marrow adipose tissue (MAT) using commercial manual software as a comparator. Also, abdominal CT scans (n = 100) were used to quantify psoas muscle volumes and intermuscular adipose tissue (IMAT) using the same software. We calculated Pearson's correlation coefficients, individual intra-class correlation coefficients (ICC), and Bland-Altman limits of agreement together with Bland-Altman plots to show the inter- and intra-observer agreement between Tissue Compass and commercially available software. In the animal study, the agreement between Tissue Compass and commercial software was r > 0.93 and ICC > 0.93 for rat femur measurements. Bland-Altman limits of agreement was - 720.89 (- 1.5e+04, 13,074.00) for MAT, 4421.11 (- 1.8e+04, 27,149.73) for HBM and - 6073.32 (- 2.9e+04, 16,388.37) for bone. The inter-observer agreement for QCT human study between two observers was r > 0.99 and ICC > 0.99. Bland-Altman limits of agreement was 0.01 (- 0.07, 0.10) for MAT in hip, 0.02 (- 0.08, 0.12) for HBM in hip, 0.05 (- 0.15, 0.25) for bone in hip, 0.02 (- 0.18, 0.22) for MAT in L1, 0.00 (- 0.16, 0.16) for HBM in L1, and 0.02 (- 0.23, 0.27) for bone in L1. The intra-observer agreement for QCT human study between the two applications was r > 0.997 and ICC > 0.99. Bland-Altman limits of agreement was 0.03 (- 0.13, 0.20) for MAT in hip, 0.05 (- 0.08, 0.18) for HBM in hip, 0.05 (- 0.24, 0.34) for bone in hip, - 0.02 (- 0.34, 0.31) for MAT in L1, - 0.14 (- 0.44, 0.17) for HBM in L1, - 0.29 (- 0.62, 0.05) for bone in L1, 0.03 (- 0.08, 0.15) for IMAT in psoas, and 0.02 (- 0.35, 0.38) for muscle in psoas. Compared to a conventional application, Tissue Compass demonstrated high accuracy and non-inferiority while also facilitating easier analyses. Tissue Compass could become the tool of choice to diagnose tissue loss/gain syndromes in the future by requiring a small number of CT sections to detect tissue volumes and fat infiltration.

Associations of Age at Menopause With Postmenopausal Bone Mineral Density and Fracture Risk in Women.

CONTEXT: Menopause before age 45 is a risk factor for fractures, but menopause occurs at age ≥45 in ~90% of women. OBJECTIVE: To determine, in women with menopause at age ≥45, whether (1) years since the final menstrual period (FMP) is more strongly associated with postmenopausal bone mineral density (BMD) than chronological age and (2) lower age at FMP is related to more fractures. DESIGN AND SETTING: The Study of Women's Health Across the Nation, a longitudinal cohort study of the menopause transition (MT). PARTICIPANTS: A diverse cohort of ambulatory women (pre- or early perimenopausal at baseline, with 15 near-annual follow-up assessments). MAIN OUTCOME MEASURES: Postmenopausal lumbar spine (LS) or femoral neck (FN) BMD (n = 1038) and time to fracture (n = 1554). RESULTS: Adjusted for age, body mass index (BMI), cigarette use, alcohol intake, baseline LS or FN BMD, baseline MT stage, and study site using multivariable linear regression, each additional year after the FMP was associated with 0.006 g/cm2 (P < 0.0001) and 0.004 g/cm2 (P < 0.0001) lower postmenopausal LS and FN BMD, respectively. Age was not related to FN BMD independent of years since FMP. In Cox proportional hazards regression, accounting for race/ethnicity, BMI, cigarette use, alcohol intake, prior fracture, diabetes status, exposure to bone-modifying medications/supplements, and study site, the hazard for incident fracture was 5% greater for each 1-year decrement in age at FMP (P = 0.02). CONCLUSIONS: Years since the FMP is more strongly associated with postmenopausal BMD than chronological age, and earlier menopause is associated with more fractures.