Supplemental Vitamin D and Incident Fractures in Midlife and Older Adults.

BACKGROUND: Vitamin D supplements are widely recommended for bone health in the general population, but data on whether they prevent fractures have been inconsistent. METHODS: In an ancillary study of the Vitamin D and Omega-3 Trial (VITAL), we tested whether supplemental vitamin D3 would result in a lower risk of fractures than placebo. VITAL was a two-by-two factorial, randomized, controlled trial that investigated whether supplemental vitamin D3 (2000 IU per day), n-3 fatty acids (1 g per day), or both would prevent cancer and cardiovascular disease in men 50 years of age or older and women 55 years of age or older in the United States. Participants were not recruited on the basis of vitamin D deficiency, low bone mass, or osteoporosis. Incident fractures were reported by participants on annual questionnaires and adjudicated by centralized medical-record review. The primary end points were incident total, nonvertebral, and hip fractures. Proportional-hazards models were used to estimate the treatment effect in intention-to-treat analyses. RESULTS: Among 25,871 participants (50.6% women [13,085 of 25,871] and 20.2% Black [5106 of 25,304]), we confirmed 1991 incident fractures in 1551 participants over a median follow-up of 5.3 years. Supplemental vitamin D3, as compared with placebo, did not have a significant effect on total fractures (which occurred in 769 of 12,927 participants in the vitamin D group and in 782 of 12,944 participants in the placebo group; hazard ratio, 0.98; 95% confidence interval [CI], 0.89 to 1.08; P = 0.70), nonvertebral fractures (hazard ratio, 0.97; 95% CI, 0.87 to 1.07; P = 0.50), or hip fractures (hazard ratio, 1.01; 95% CI, 0.70 to 1.47; P = 0.96). There was no modification of the treatment effect according to baseline characteristics, including age, sex, race or ethnic group, body-mass index, or serum 25-hydroxyvitamin D levels. There were no substantial between-group differences in adverse events as assessed in the parent trial. CONCLUSIONS: Vitamin D3 supplementation did not result in a significantly lower risk of fractures than placebo among generally healthy midlife and older adults who were not selected for vitamin D deficiency, low bone mass, or osteoporosis. (Funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases; VITAL ClinicalTrials.gov number, NCT01704859.).

Atypical Femur Fracture Risk versus Fragility Fracture Prevention with Bisphosphonates.

BACKGROUND: Bisphosphonates are effective in reducing hip and osteoporotic fractures. However, concerns about atypical femur fractures have contributed to substantially decreased bisphosphonate use, and the incidence of hip fractures may be increasing. Important uncertainties remain regarding the association between atypical femur fractures and bisphosphonates and other risk factors. METHODS: We studied women 50 years of age or older who were receiving bisphosphonates and who were enrolled in the Kaiser Permanente Southern California health care system; women were followed from January 1, 2007, to November 30, 2017. The primary outcome was atypical femur fracture. Data on risk factors, including bisphosphonate use, were obtained from electronic health records. Fractures were radiographically adjudicated. Multivariable Cox models were used. The risk-benefit profile was modeled for 1 to 10 years of bisphosphonate use to compare associated atypical fractures with other fractures prevented. RESULTS: Among 196,129 women, 277 atypical femur fractures occurred. After multivariable adjustment, the risk of atypical fracture increased with longer duration of bisphosphonate use: the hazard ratio as compared with less than 3 months increased from 8.86 (95% confidence interval [CI], 2.79 to 28.20) for 3 years to less than 5 years to 43.51 (95% CI, 13.70 to 138.15) for 8 years or more. Other risk factors included race (hazard ratio for Asians vs. Whites, 4.84; 95% CI, 3.57 to 6.56), height, weight, and glucocorticoid use. Bisphosphonate discontinuation was associated with a rapid decrease in the risk of atypical fracture. Decreases in the risk of osteoporotic and hip fractures during 1 to 10 years of bisphosphonate use far outweighed the increased risk of atypical fracture among Whites but less so among Asians. After 3 years, 149 hip fractures were prevented and 2 bisphosphonate-associated atypical fractures occurred in Whites, as compared with 91 and 8, respectively, in Asians. CONCLUSIONS: The risk of atypical femur fracture increased with longer duration of bisphosphonate use and rapidly decreased after bisphosphonate discontinuation. Asians had a higher risk than Whites. The absolute risk of atypical femur fracture remained very low as compared with reductions in the risk of hip and other fractures with bisphosphonate treatment. (Funded by Kaiser Permanente and others.).

Systems genetics analysis defines importance of TMEM43/LUMA for cardiac- and metabolic-related pathways.

Broad cellular functions and diseases including muscular dystrophy, arrhythmogenic right ventricular cardiomyopathy (ARVC5) and cancer are associated with transmembrane protein43 (TMEM43/LUMA). The study aimed to investigate biological roles of TMEM43 through genetic regulation, gene pathways and gene networks, candidate interacting genes, and up- or downstream regulators. Cardiac transcriptomes from 40 strains of recombinant inbred BXD mice and two parental strains representing murine genetic reference population (GRP) were applied for genetic correlation, functional enrichment, and coexpression network analysis using systems genetics approach. The results were validated in a newly created knock-in Tmem43-S358L mutation mouse model (Tmem43S358L) that displayed signs of cardiac dysfunction, resembling ARVC5 phenotype seen in humans. We found high Tmem43 levels among BXDs with broad variability in expression. Expression of Tmem43 highly negatively correlated with heart mass and heart rate among BXDs, whereas levels of Tmem43 highly positively correlated with plasma high-density lipoproteins (HDL). Through finding differentially expressed genes (DEGs) between Tmem43S358L mutant and wild-type (Tmem43WT) lines, 18 pathways (out of 42 found in BXDs GRP) that are involved in ARVC, hypertrophic cardiomyopathy, dilated cardiomyopathy, nonalcoholic fatty liver disease, Alzheimer's disease, Parkinson's disease, and Huntington's disease were verified. We further constructed Tmem43-mediated gene network, in which Ctnna1, Adcy6, Gnas, Ndufs6, and Uqcrc2 were significantly altered in Tmem43S358L mice versus Tmem43WT controls. Our study defined the importance of Tmem43 for cardiac- and metabolism-related pathways, suggesting that cardiovascular disease-relevant risk factors may also increase risk of metabolic and neurodegenerative diseases via TMEM43-mediated pathways.

Outcomes post fragility fracture among members of an integrated healthcare organization.

This study highlights an unmet need in osteoporosis management, suggesting that beyond bone mineral density and fracture history, gender, fracture type, and age should be considered for fracture risk assessment. Following fragility fracture, men, patients with a spine or hip fracture, and those aged ≥ 65 have a higher disease burden. INTRODUCTION: The objective of this study was to characterize osteoporosis-related fracture incidence and identify predictors of subsequent fractures and mortality. METHODS: This retrospective cohort study, conducted within Kaiser Permanente Southern California, included patients aged ≥ 50 years with qualifying fractures from 1/1/2007 to 12/31/2016, identified from diagnosis/procedure codes. Rates for fracture incidence, mortality, and resource utilization in the year post-fracture are reported. Associations between index fracture types and demographic/clinical characteristics, and mortality, subsequent fracture, and rehospitalization outcomes were estimated. RESULTS: Of 63,755 eligible patients, 66.7% were ≥ 65 years and 69.1% female. Index fractures included nonhip/nonspine (64.4%), hip (25.3%), and spine (10.3%). Age-adjusted subsequent fracture rate/100 person-years was higher for those with an index spine (14.5) versus hip fracture (6.3). Hospitalization rate/100 person-years was highest for patients ≥ 65 (31.8) and for spine fractures (43.5). Men (vs women) had higher age-adjusted rates of hospitalization (19.4; 17.7), emergency room visits (73.8; 66.3), and use of rehabilitation services (31.7; 27.2). The 30-day age-adjusted mortality rate/100 person-years was 46.7, 32.4, and 15.5 for spine, hip, and nonspine/nonhip fractures. The 1-year age-adjusted mortality rate/100 person-years was 14.7 for spine and 15.6 for hip fractures. In multivariable analyses, spine and hip fractures (vs nonhip/nonspine fractures) were significant predictors of 1-year mortality, all-cause and osteoporosis-related hospitalization, and nursing home use (all P-values < 0.0001). CONCLUSION: Morbidity is high in the year following a fragility fracture and men, patients with a spine or hip fracture, and those aged ≥ 65 have a greater disease burden.

Hematopoietic cell transplant for reversal of liver fibrosis in a pediatric patient with erythropoietic protoporphyria.

BACKGROUND: EPP is a rare disorder of heme biosynthesis in which patients present with disabling photosensitivity. A subset of patients develop severe liver disease with progressive liver failure necessitating an OLT. A HCT can potentially cure EPP by replacing the native bone marrow, which is the primary site of heme synthesis. However, due to concerns for inherent risks of treatment-related toxicities, the use of HCT has been reserved for patients undergoing an OLT to avoid disease recurrence in the hepatic graft. Data for HCT in EPP are lacking, particularly in the pediatric population. CASE (METHODS/RESULTS): We present the case of a 12-year-old patient with EPP photosensitivity and cirrhosis, whom we successfully treated with pre-emptive allogeneic HCT, significantly improving the patient's quality of life. We used a matched-unrelated donor bone marrow-derived graft. Our patient achieved full donor peripheral blood chimerism and has not had any evidence of GVHD. In addition to resolution of photosensitivity, our patient had reversal of liver fibrosis which we feel was largely due to intervention at an early stage of compensated cirrhosis. CONCLUSION: Our case highlights the successful application of a known RIC regimen to this rare disorder that was well tolerated with sustained donor engraftment. It also emphasizes the importance of timing for HCT in patients with EPP and liver fibrosis. HCT should be considered early in pediatric patients with EPP-hepatopathy to prevent progression to liver failure and need for OLT with lifelong immunosuppression.

A novel effervescent formulation of oral weekly alendronate (70 mg) improves persistence compared to alendronate tablets in post-menopausal women with osteoporosis.

BACKGROUND: A novel effervescent buffered solution of 70 mg alendronate (ALN-EX) was developed to improve upper gastrointestinal (GI) tolerability over alendronate tablets (ALN-T). Whether a better GI tolerability can improve persistence remains to be determined. AIM: This study evaluated persistence and reasons for discontinuation in patients treated with ALN-EX compared to a historical cohort on ALN-T. METHODS: Post-menopausal women (PMW) from a standardized clinical database with BMD T-score < -2.5, or between -2 and -2.5 and at least one vertebral fracture, starting ALN-EX between July 2015 and June 2016 were included. A historical cohort comprised of randomly selected and age-matched PMW on ALN-T was used as a control. Persistence at 6 and 12 months and reasons for discontinuation (e.g. adverse events; AE) were compared between the two groups. RESULTS: A total of 144 PMW on ALN-EX and 216 PMW on ALN-T were analysed. Persistence at 6 and 12 months was 91% and 81% in the ALN-EX group vs. 75% and 69% in the ALN-T group, this difference attaining statistical significance at both 6- (p < 0.001) and 12 months (p = 0.009). A significantly higher proportion of patients receiving ALN-T discontinued treatment due to GI AEs (4% ALN-EX vs. 11% ALN-T; p = 0.027), or patient's decision to discontinue (6% ALN-EX vs. 13% ALN-T; p = 0.016). The adjusted odds ratio of persisting on ALN-EX treatment at 12 months was 2.02 (95% CI: 1.21-3.41, p = 0.008). CONCLUSION: Our findings demonstrate that ALN-EX can provide greater persistence and improved tolerability compared to ALN-T, allowing it to be a viable alternative option in the management of osteoporosis.

Clinical Practice. Postmenopausal Osteoporosis.

Key Clinical Points Postmenopausal Osteoporosis Fractures and osteoporosis are common, particularly among older women, and hip fractures can be devastating. Treatment is generally recommended in postmenopausal women who have a bone mineral density T score of -2.5 or less, a history of spine or hip fracture, or a Fracture Risk Assessment Tool (FRAX) score indicating increased fracture risk. Bisphosphonates (generic) and denosumab reduce the risk of hip, nonvertebral, and vertebral fractures; bisphosphonates are commonly used as first-line treatment in women who do not have contraindications. Teriparatide reduces the risk of nonvertebral and vertebral fractures. Osteonecrosis of the jaw and atypical femur fractures have been reported with treatment but are rare. The benefit-to-risk ratio for osteoporosis treatment is strongly positive for most women with osteoporosis. Because benefits are retained after discontinuation of alendronate or zoledronic acid, drug holidays after 5 years of alendronate therapy or 3 years of zoledronic acid therapy may be considered for patients at lower risk for fracture.

Maternal Black Race and Persistent Wheezing Illness in Former Extremely Low Gestational Age Newborns: Secondary Analysis of a Randomized Trial.

OBJECTIVE: To evaluate the relationship between maternal self-reported race/ethnicity and persistent wheezing illness in former high-risk, extremely low gestational age newborns, and to quantify the contribution of socioeconomic, environmental, and biological factors on this relationship. STUDY DESIGN: We assessed persistent wheezing illness determined at 18-24 months corrected (for prematurity) age in survivors of a randomized trial. Parents/caregivers were surveyed for wheeze and inhaled asthma medication use quarterly to 12 months, and at 18 and 24 months. We used multivariable analysis to evaluate the relationship of maternal race to persistent wheezing illness, and identified mediators for this relationship via formal mediation analysis. RESULTS: Of 420 infants (25.2 ± 1.2 weeks of gestation and 714 ± 166 g at birth, 57% male, 34% maternal black race), 189 (45%) had persistent wheezing illness. After adjustment for gestational age, birth weight, and sex, infants of black mothers had increased odds of persistent wheeze compared with infants of nonblack mothers (OR = 2.9, 95% CI 1.9, 4.5). Only bronchopulmonary dysplasia, breast milk diet, and public insurance status were identified as mediators. In this model, the direct effect of race accounted for 69% of the relationship between maternal race and persistent wheeze, whereas breast milk diet, public insurance status, and bronchopulmonary dysplasia accounted for 8%, 12%, and 10%, respectively. CONCLUSIONS: Among former high-risk extremely low gestational age newborns, infants of black mothers have increased odds of developing persistent wheeze. A substantial proportion of this effect is directly accounted for by race, which may reflect unmeasured environmental influences, and acquired and innate biological differences. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01022580.

The Randomized, Controlled Trial of Late Surfactant: Effects on Respiratory Outcomes at 1-Year Corrected Age.

OBJECTIVE: To determine the effects of late surfactant on respiratory outcomes determined at 1-year corrected age in the Trial of Late Surfactant (TOLSURF), which randomized newborns of extremely low gestational age (≤28 weeks' gestational age) ventilated at 7-14 days to late surfactant and inhaled nitric oxide vs inhaled nitric oxide-alone (control). STUDY DESIGN: Caregivers were surveyed in a double-blinded manner at 3, 6, 9, and 12 months' corrected age to collect information on respiratory resource use (infant medication use, home support, and hospitalization). Infants were classified for composite outcomes of pulmonary morbidity (no PM, determined in infants with no reported respiratory resource use) and persistent PM (determined in infants with any resource use in ≥3 surveys). RESULTS: Infants (n = 450, late surfactant n = 217, control n = 233) were 25.3 ± 1.2 weeks' gestation and 713 ± 164 g at birth. In the late surfactant group, fewer infants received home respiratory support than in the control group (35.8% vs 52.9%, relative benefit [RB] 1.28 [95% CI 1.07-1.55]). There was no benefit of late surfactant for No PM vs PM (RB 1.27; 95% CI 0.89-1.81) or no persistent PM vs persistent PM (RB 1.01; 95% CI 0.87-1.17). After adjustment for imbalances in baseline characteristics, relative benefit of late surfactant treatment increased: RB 1.40 (95% CI 0.89-1.80) for no PM and RB 1.24 (95% CI 1.08-1.42) for no persistent PM. CONCLUSION: Treatment of newborns of extremely low gestational age with late surfactant in combination with inhaled nitric oxide decreased use of home respiratory support and may decrease persistent pulmonary morbidity. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01022580.

Pharmacogenomics of estrogens on changes in carotid artery intima-medial thickness and coronary arterial calcification: Kronos Early Estrogen Prevention Study.

Prior to the initiation of menopausal hormone treatment (MHT), genetic variations in the innate immunity pathway were found to be associated with carotid artery intima-medial thickness (CIMT) and coronary arterial calcification (CAC) in women (n = 606) enrolled in the Kronos Early Estrogen Prevention Study (KEEPS). Whether MHT might affect these associations is unknown. The association of treatment outcomes with variation in the same 764 candidate genes was evaluated in the same KEEPS participants 4 yr after randomization to either oral conjugated equine estrogens (0.45 mg/day), transdermal 17ß-estradiol (50 µg/day), each with progesterone (200 mg/day) for 12 days each month, or placebo pills and patch. Twenty SNPs within the innate immunity pathway most related with CIMT after 4 yr were not among those associated with CIMT prior to MHT. In 403 women who completed the study in their assigned treatment group, single nucleotide polymorphisms (SNPs) within the innate immunity pathway were found to alter the treatment effect on 4 yr change in CIMT (i.e., significant interaction between treatment and genetic variation in the innate immunity pathway; P < 0.001). No SNPs by treatment effects were observed with changes of CAC >5 Agatston units after 4 yr. Results of this study suggest that hormonal status may interact with genetic variants to influence cardiovascular phenotypes, specifically, the pharmacogenomic effects within the innate immunity pathway for CIMT.

Early Cumulative Supplemental Oxygen Predicts Bronchopulmonary Dysplasia in High Risk Extremely Low Gestational Age Newborns.

OBJECTIVE: To assess the prognostic accuracy of early cumulative supplemental oxygen (CSO) exposure for prediction of bronchopulmonary dysplasia (BPD) or death, and to evaluate the independent association of CSO with BPD or death. STUDY DESIGN: We performed a secondary analysis of the Trial of Late Surfactant, which enrolled 511 infants born at ≤28 weeks gestational age who were mechanically ventilated at 7-14 days of life. Our primary outcome was BPD or death at 36 weeks postmenstrual age, as determined by a physiological oxygen/flow challenge. Average daily supplemental oxygen (fraction of inspired oxygen - 0.21) was calculated. CSO was calculated as the sum of the average daily supplemental oxygen over time periods of interest up to 28 days of age. Area under the receiver operating curve (AUROC) values were generated to evaluate the accuracy of CSO for prediction of BPD or death. The independent relationship between CSO and BPD or death was assessed in multivariate modeling, while adjusting for mean airway pressure. RESULTS: In the study infants, mean gestational age at birth was 25.2 ± 1.2 weeks and mean birth weight was 700 ± 165 g. The AUROC value for CSO at 14 days was significantly better than that at earlier time points for outcome prediction (OR, 0.70; 95% CI, 0.65-0.74); it did not increase with the addition of later data. In multivariate modeling, a CSO increase of 1 at 14 days increased the odds of BPD or death (OR, 1.7; 95% CI, 1.3-2.2; P < .0001), which corresponds to a 7% higher daily supplemental oxygen value. CONCLUSION: In high-risk extremely low gestational age newborns, the predictive accuracy of CSO plateaus at 14 days. CSO is independently associated with BPD or death. This index may identify infants who could benefit from early intervention to prevent BPD.

Randomized Trial of Late Surfactant Treatment in Ventilated Preterm Infants Receiving Inhaled Nitric Oxide.

OBJECTIVE: To assess whether late surfactant treatment in extremely low gestational age (GA) newborn infants requiring ventilation at 7-14 days, who often have surfactant deficiency and dysfunction, safely improves survival without bronchopulmonary dysplasia (BPD). STUDY DESIGN: Extremely low GA newborn infants (GA ≤28 0/7 weeks) who required mechanical ventilation at 7-14 days were enrolled in a randomized, masked controlled trial at 25 US centers. All infants received inhaled nitric oxide and either surfactant (calfactant/Infasurf) or sham instillation every 1-3 days to a maximum of 5 doses while intubated. The primary outcome was survival at 36 weeks postmenstrual age (PMA) without BPD, as evaluated by physiological oxygen/flow reduction. RESULTS: A total of 511 infants were enrolled between January 2010 and September 2013. There were no differences between the treated and control groups in mean birth weight (701 ± 164 g), GA (25.2 ± 1.2 weeks), percentage born at GA <26 weeks (70.6%), race, sex, severity of lung disease at enrollment, or comorbidities of prematurity. Survival without BPD did not differ between the treated and control groups at 36 weeks PMA (31.3% vs 31.7%; relative benefit, 0.98; 95% CI, 0.75-1.28; P = .89) or 40 weeks PMA (58.7% vs 54.1%; relative benefit, 1.08; 95% CI, 0.92-1.27; P = .33). There were no between-group differences in serious adverse events, comorbidities of prematurity, or severity of lung disease to 36 weeks. CONCLUSION: Late treatment with up to 5 doses of surfactant in ventilated premature infants receiving inhaled nitric oxide was well tolerated, but did not improve survival without BPD at 36 or 40 weeks. Pulmonary and neurodevelopmental assessments are ongoing. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01022580.

Role of PPARα in the attenuation of bile acid-induced apoptosis by omega-3 long-chain polyunsaturated fatty acids in cultured hepatocytes.

BACKGROUND: Omega-3 long-chain polyunsaturated fatty acids (ω3PUFA) have been shown to be antiinflammatory in the attenuation of hepatocellular injury. Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor transcription factor that inhibits the activation of nuclear factor κB, thereby repressing inflammation, and ωPUFA are PPARα ligands. The purpose of this study was to determine if ω3PUFA attenuate bile acid-induced apoptosis via PPARα. METHODS: Human hepatocellular carcinoma (HepG2) cells were treated with chenodeoxycholic acid (CDCA) ± ω3PUFA. Activation of PPARα was evaluated, and expression of PPARα, farnesoid X receptor, liver X receptor alpha (LXRα), and retinoid X receptor mRNA was evaluated by reverse-transcriptase PCR. RESULTS: PPARα activation was increased in HepG2 cells treated with ω3PUFA, and decreased in the presence of CDCA when compared with untreated cells. PPARα mRNA was reduced by 67% with CDCA and restored to the level of control with ω3PUFA. LXRα mRNA increased twofold with CDCA treatment and was significantly reduced by ω3PUFA. CONCLUSION: Expression of PPARα, as well as LXRα mRNA levels, was reduced with CDCA treatment and restored with the addition of ω3PUFA. These results suggest that PPARα and LXRα may be mediators by which ω3PUFA attenuate bile acid-induced hepatocellular injury.

Prevalence of osteoporosis in the Italian population and main risk factors: results of BoneTour Campaign.

BACKGROUND: BoneTour is a campaign conducted throughout the Italian territory for the assessment of Italian people bone status and for the prevention of osteoporosis. METHODS: A total of 7305 sequential subjects of both sexes were screened, collecting clinical data through the FRAX™ questionnaire, and measuring heel bone stiffness by Quantitative Ultrasonography (QUS). The 10-year risk for hip and major osteoporotic fractures was calculated taking into account personal or family history of fragility fracture, smoking, alcohol abuse, rheumatoid arthritis, prolonged steroids assumption. Additional risk factors were evaluated, including early menopause, poor sunlight exposure, low dietary calcium intake, physical inactivity, number of pregnancies, months of lactation, tobacco cigarettes smoked per year, specific causes of secondary osteoporosis. Through a correlation study, the influence of each factor on the development of osteoporosis was analyzed. RESULTS: As many as 18 % of women suffer from osteoporosis, as defined by QUS T-score. The calculation of FRAX™ confirmed the weight of the already known risk factors. The correlation study revealed the significance of some additional factors, such as hyperthyroidism, nephrolithiasis, Crohn disease, ulcerative colitis, celiac disease, poor sun exposure, and oophorectomy before age 50. CONCLUSIONS: The high prevalence of secondary osteoporosis in the Italian population clearly indicates the importance of additional risk factors not yet included in the FRAX™ algorithm, for which preventive measures should be considered. Screening campaigns may allow both early diagnosis and access to treatment.

Effects of Hormone Therapy on Cognition and Mood in Recently Postmenopausal Women: Findings from the Randomized, Controlled KEEPS-Cognitive and Affective Study.

BACKGROUND: Menopausal hormone therapy (MHT) reportedly increases the risk of cognitive decline in women over age 65 y. It is unknown whether similar risks exist for recently postmenopausal women, and whether MHT affects mood in younger women. The ancillary Cognitive and Affective Study (KEEPS-Cog) of the Kronos Early Estrogen Prevention Study (KEEPS) examined the effects of up to 4 y of MHT on cognition and mood in recently postmenopausal women. METHODS AND FINDINGS: KEEPS, a randomized, double-blinded, placebo-controlled clinical trial, was conducted at nine US academic centers. Of the 727 women enrolled in KEEPS, 693 (95.3%) participated in the ancillary KEEPS-Cog, with 220 women randomized to receive 4 y of 0.45 mg/d oral conjugated equine estrogens (o-CEE) plus 200 mg/d micronized progesterone (m-P) for the first 12 d of each month, 211 women randomized to receive 50 µg/d transdermal estradiol (t-E2) plus 200 mg/d m-P for the first 12 d of each month, and 262 women randomized to receive placebo pills and patches. Primary outcomes included the Modified Mini-Mental State examination; four cognitive factors: verbal learning/memory, auditory attention/working memory, visual attention/executive function, and speeded language/mental flexibility; and a mood measure, the Profile of Mood States (POMS). MHT effects were analyzed using linear mixed-effects (LME) models, which make full use of all available data from each participant, including those with missing data. Data from those with and without full data were compared to assess for potential biases resulting from missing observations. For statistically significant results, we calculated effect sizes (ESs) to evaluate the magnitude of changes. On average, participants were 52.6 y old, and 1.4 y past their last menstrual period. By month 48, 169 (24.4%) and 158 (22.8%) of the 693 women who consented for ancillary KEEPS-Cog were lost to follow-up for cognitive assessment (3MS and cognitive factors) and mood evaluations (POMS), respectively. However, because LME models make full use all available data, including data from women with missing data, 95.5% of participants were included in the final analysis (n = 662 in cognitive analyses, and n = 661 in mood analyses). To be included in analyses, women must have provided baseline data, and data from at least one post-baseline visit. The mean length of follow-up was 2.85 y (standard deviation [SD] = 0.49) for cognitive outcomes and 2.76 (SD = 0.57) for mood outcomes. No treatment-related benefits were found on cognitive outcomes. For mood, model estimates indicated that women treated with o-CEE showed improvements in depression and anxiety symptoms over the 48 mo of treatment, compared to women on placebo. The model estimate for the depression subscale was -5.36 × 10(-2) (95% CI, -8.27 × 10(-2) to -2.44 × 10(-2); ES = 0.49, p < 0.001) and for the anxiety subscale was -3.01 × 10(-2) (95% CI, -5.09 × 10(-2) to -9.34 × 10(-3); ES = 0.26, p < 0.001). Mood outcomes for women randomized to t-E2 were similar to those for women on placebo. Importantly, the KEEPS-Cog results cannot be extrapolated to treatment longer than 4 y. CONCLUSIONS: The KEEPS-Cog findings suggest that for recently postmenopausal women, MHT did not alter cognition as hypothesized. However, beneficial mood effects with small to medium ESs were noted with 4 y of o-CEE, but not with 4 y of t-E2. The generalizability of these findings is limited to recently postmenopausal women with low cardiovascular risk profiles. TRIAL REGISTRATION: ClinicalTrials.gov NCT00154180 and NCT00623311.

Arterial imaging outcomes and cardiovascular risk factors in recently menopausal women: a randomized trial.

BACKGROUND: Whether menopausal hormone therapy (MHT) protects against cardiovascular disease (CVD) remains unclear. OBJECTIVE: To assess atherosclerosis progression and CVD risk factors after MHT initiated in early menopause. DESIGN: Randomized, controlled trial. (ClinicalTrials.gov: NCT00154180). SETTING: Nine U.S. academic centers. PARTICIPANTS: Healthy menopausal women aged 42 to 58 years between 6 and 36 months from last menses without prior CVD events who had a coronary artery calcium (CAC) score less than 50 Agatston units and had not received estrogen or lipid-lowering therapy for at least 90 days. INTERVENTION: Oral conjugated equine estrogens (o-CEE), 0.45 mg/d, or transdermal 17ß-estradiol (t-E2), 50 mcg/d, each with 200 mg of oral progesterone for 12 days per month, or placebo for 48 months. MEASUREMENTS: Primary end point was annual change in carotid artery intima-media thickness (CIMT). Secondary end points included changes in markers of CVD risk. RESULTS: Of 727 randomly assigned women, 89.3% had at least 1 follow-up CIMT and 79.8% had CIMT at 48 months. Mean CIMT increases of 0.007 mm/y were similar across groups. The percentages of participants in whom CAC score increased did not differ significantly across groups. No changes in blood pressure were observed with o-CEE or t-E2. Low- and high-density lipoprotein cholesterol levels improved and levels of C-reactive protein and sex hormone-binding globulin but not interleukin-6 increased with o-CEE. Insulin resistance decreased with t-E2. Serious adverse events did not differ by treatment. LIMITATION: Power to compare clinical events was insufficient. CONCLUSION: Four years of early MHT did not affect progression of atherosclerosis despite improving some markers of CVD risk. PRIMARY FUNDING SOURCE: Aurora Foundation.

Inhaled nitric oxide increases urinary nitric oxide metabolites and cyclic guanosine monophosphate in premature infants: relationship to pulmonary outcome.

OBJECTIVE: Inhaled nitric oxide (iNO) has been tested to prevent bronchopulmonary dysplasia (BPD) in premature infants, however, the role of cyclic guanosine monophosphate (cGMP) is not known. We hypothesized that levels of NO metabolites (NOx) and cGMP in urine, as a noninvasive source for biospecimen collection, would reflect the dose of iNO and relate to pulmonary outcome. STUDY DESIGN: Studies were performed on 125 infants who required mechanical ventilation at 7 to 14 days and received 24 days of iNO at 20-2 ppm. A control group of 19 infants did not receive iNO. RESULTS: In NO-treated infants there was a dose-dependent increase of both NOx and cGMP per creatinine (maximal 3.1- and 2-fold, respectively, at 10-20 ppm iNO) compared with off iNO. NOx and cGMP concentrations at both 2 ppm and off iNO were inversely related to severity of lung disease during the 1st month, and the NOx levels were lower in infants who died or developed BPD at term. NOx was higher in Caucasian compared with other infants at all iNO doses. CONCLUSION: Urinary NOx and cGMP are biomarkers of endogenous NO production and lung uptake of iNO, and some levels reflect the severity of lung disease. These results support a role of the NO-cGMP pathway in lung development.

Fracture risk in diabetic elderly men: the MrOS study.

AIMS/HYPOTHESIS: Diabetes mellitus is associated with increased fracture risk in women but few studies are available in men. To evaluate the relationship between diabetes and prospective non-vertebral fractures in elderly men, we used data from the Osteoporotic Fractures in Men (MrOS) study. METHODS: The MrOS enrolled 5,994 men (aged ≥65 years). Diabetes (ascertained by self-report, the use of medication for diabetes or an elevated fasting glucose level) was reported in 881 individuals, 80 of whom were using insulin. Hip and spine bone mineral density (BMD) was measured using dual x-ray absorptiometry (DXA). After recruitment, the men were followed for incident non-vertebral fractures using a triannual (3 yearly) questionnaire for an average of 9.1 (SD 2.7) years. The Cox proportional hazards model was used to assess the incident risk of fractures. RESULTS: In models adjusted for age, race, clinic site and total hip BMD, the risk of non-vertebral fracture was higher in men with diabetes compared with normoglycaemic men (HR 1.30, 95% CI 1.09, 1.54) and was elevated in men using insulin (HR 2.46, 95% CI 1.69, 3.59). Men with impaired fasting glucose did not have a higher risk of fracture compared with normoglycaemic men (HR 1.04, 95% CI 0.89, 1.21). After multivariable adjustment, the risk of non-vertebral fracture remained higher only among men with diabetes who were using insulin (HR 1.74, 95% CI 1.13, 2.69). CONCLUSIONS/INTERPRETATION: Men with diabetes who are using insulin have an increased risk of non-vertebral fracture for a given age and BMD.