Dennis M Black

University of California, San Francisco, San Francisco, California, United States

Are you Dennis M Black?

Claim your profile

Publications (302)2924.12 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Data concerning the link between severity of abdominal aortic calcification (AAC) and fracture risk in postmenopausal women are discordant. This association may vary by skeletal site and duration of follow-up. Our aim was to assess the association between the AAC severity and fracture risk in older women over the short- and long-term. This is a case-cohort study nested in a large multicenter prospective cohort study. The association between AAC and fracture was assessed using Odds Ratios (OR) and 95% confidence intervals (95%CI) for vertebral fractures and using Hazard Risks (HR) and 95%CI for non-vertebral and hip fractures. AAC severity was evaluated from lateral spine radiographs using Kauppila's semiquantitative score. Severe AAC (AAC score 5+) was associated with higher risk of vertebral fracture during 4 years of follow-up, after adjustment for confounders (age, BMI, walking, smoking, hip bone mineral density, prevalent vertebral fracture, systolic blood pressure, hormone replacement therapy) (OR=2.31, 95%CI: 1.24-4.30, p<0.01). In a similar model, severe AAC was associated with an increased in the hip fracture risk (HR=2.88, 95%CI: 1.00-8.36, p=0.05). AAC was not associated with the risk of any non-vertebral fracture. AAC was not associated with the fracture risk after 15-years of follow-up. In elderly women, severe AAC is associated with higher short-term risk of vertebral and hip fractures, but not with the long-term risk of these fractures. There is no association between AAC and risk of non-vertebral-non-hip fracture in older women. Our findings lend further support to the hypothesis that AAC and skeletal fragility are related. Copyright © 2015. Published by Elsevier Inc.
    Bone 06/2015; DOI:10.1016/j.bone.2015.06.019 · 4.46 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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. 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. 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. ClinicalTrials.gov NCT00154180 and NCT00623311.
    PLoS Medicine 06/2015; 12(6):e1001833. DOI:10.1371/journal.pmed.1001833 · 14.00 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hip fracture risk is known to be related to material properties of the proximal femur, but fracture prediction studies adding richer quantitative computed tomography (QCT) measures to dual energy X-ray (DXA)-based methods have shown limited improvement. Fracture types have distinct relationships to predictors, but few studies have sub-divided fracture into types, since this necessitates regional measurements and more fracture cases. This work makes use of cortical bone mapping (CBM) to accurately assess, with no prior anatomical presumptions, the distribution of properties related to fracture type. CBM uses QCT data to measure the cortical and trabecular properties, accurate even for thin cortices below the imaging resolution. The osteoporotic fractures in men (MrOS) study is a predictive case-cohort study of men over 65: we analyse 99 fracture cases (44 trochanteric and 55 femoral neck) compared to a cohort of 308, randomly selected from 5,994. To our knowledge, this is the largest QCT-based predictive hip fracture study to date, and the first to incorporate CBM analysis into fracture prediction. We demonstrate that both cortical mass surface density, and endocortical trabecular BMD, show significant difference in fracture cases vs. cohort, in regions appropriate to fracture type. We incorporate these regions into predictive models using Cox proportional hazards regression to estimate hazard ratios, and logistic regression to estimate area under the receiver operating characteristic curve (AUC). Adding CBM to DXA-based BMD leads to a small but significant (p < 0.005) improvement in model prediction for any fracture, with AUC increasing from 0.78 to 0.79, assessed using leave-one-out cross-validation. For specific fracture types, the improvement is more significant (p < 0.0001), with AUC increasing from 0.71 to 0.77 (trochanteric fractures) and 0.76 to 0.82 (femoral neck fractures). In contrast, adding DXA-based BMD to a CBM-based predictive model does not result in any significant improvement. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 05/2015; DOI:10.1002/jbmr.2552 · 6.59 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: While bisphosphonates reduce fracture risk over 3 to 5 years, the optimal duration of treatment is uncertain. In a randomized extension study (E1) of the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly−Pivotal Fracture Trial (HORIZON−PFT), zoledronic acid (ZOL) 5 mg annually for 6 years showed maintenance of bone mineral density (BMD), decrease in morphometric vertebral fractures, and a modest reduction in bone turnover markers (BTMs) compared with discontinuation after 3 years. To investigate the longer-term efficacy and safety of ZOL, a second extension (E2) was conducted to 9 years in which women on ZOL for 6 years in E1 were randomized to either ZOL (Z9) or placebo (Z6P3) for 3 additional years. In this multicenter, randomized, double-blind study, 190 women were randomized to Z9 (n = 95) and Z6P3 (n = 95). The primary endpoint was change in total hip BMD at year 9 vs. year 6 in Z9 compared with Z6P3. Other secondary endpoints included fractures, BTMs, and safety. From year 6 to 9, the mean change in total hip BMD was −0.54% in Z9 vs. −1.31% in Z6P3 (difference 0.78%; 95% confidence interval [CI]: −0.37%, 1.93%; p = 0.183). BTMs showed small, non-significant increases in those who discontinued after 6 years compared with those who continued for 9 years. The number of fractures was low and did not significantly differ by treatment. While generally safe, there was a small increase in cardiac arrhythmias (combined serious and non-serious) in the Z9 group but no significant imbalance in other safety parameters. The results suggest almost all patients who have received six annual ZOL infusions can stop medication for up to 3 years with apparent maintenance of benefits. © 2015 American Society for Bone and Mineral Research.
    Journal of Bone and Mineral Research 05/2015; 30(5):934–944. DOI:10.1002/jbmr.2442 · 6.59 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Roux-en-Y gastric bypass (RYGB) surgery has negative effects on bone, mediated in part by effects on nutrient absorption. Not only can RYGB result in vitamin D malabsorption, but also the bypassed duodenum and proximal jejunum are the predominant sites of active, transcellular, 1,25(OH)2D-mediated calcium (Ca) uptake. However, Ca absorption occurs throughout the intestine, and those who undergo RYGB might maintain sufficient Ca absorption, particularly if vitamin D status and Ca intake are robust. We determined the effects of RYGB on intestinal fractional Ca absorption (FCA) while maintaining ample 25OHD levels (goal ≥30 ng/mL) and Ca intake (1200 mg daily) in a prospective cohort of 33 obese adults (BMI 44.7 ± 7.4 kg/m2). FCA was measured pre-operatively and 6 months post-operatively with a dual stable isotope method. Other measures included calciotropic hormones, bone turnover markers, and BMD by DXA and QCT. Mean 6-month weight loss was 32.5 ± 8.4 kg (25.8% ± 5.2% of pre-operative weight). FCA decreased from 32.7% ± 14.0% pre-operatively to 6.9% ± 3.8% post-operatively (p < 0.0001), despite median (interquartile range) 25OHD levels of 41.0 (33.1-48.5) and 36.5 (28.8-40.4) ng/mL, respectively. Consistent with the FCA decline, 24-hour urinary Ca decreased, PTH increased, and 1,25(OH)2D increased (p≤0.02). Bone turnover markers increased markedly, areal BMD decreased at the proximal femur, and volumetric BMD decreased at the spine (p < 0.001). Those with lower post-operative FCA had greater increases in serum CTx (ρ = -0.43, p = 0.01). Declines in FCA and BMD were not correlated over the 6 months. In conclusion, FCA decreased dramatically after RYGB, even with most 25OHD levels ≥30 ng/mL and with recommended Ca intake. RYGB patients may need high Ca intakes to prevent perturbations in Ca homeostasis, although the approach to Ca supplementation needs further study. Decline in FCA could contribute to the decline in BMD after RYGB, and strategies to avoid long-term skeletal consequences should be investigated. This article is protected by copyright. All rights reserved
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 01/2015; DOI:10.1002/jbmr.2467 · 6.59 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Bone marrow fat may serve a metabolic role distinct from other fat depots, and it may be altered by metabolic conditions including diabetes. Caloric restriction paradoxically increases marrow fat in mice, and women with anorexia nervosa have high marrow fat. The longitudinal effect of weight loss on marrow fat in humans is unknown. We hypothesized that marrow fat increases after Roux-en-Y gastric bypass (RYGB) surgery, as total body fat decreases. In a pilot study of 11 morbidly obese women (6 diabetic, 5 nondiabetic), we measured vertebral marrow fat content (percentage fat fraction) before and 6months after RYGB using magnetic resonance spectroscopy. Total body fat mass declined in all participants (mean±SD decline 19.1±6.1kg or 36.5±10.9%, p<0.001). Areal bone mineral density (BMD) decreased by 5.2±3.5% and 4.1±2.6% at the femoral neck and total hip, respectively, and volumetric BMD decreased at the spine by 7.4±2.8% (p<0.001 for all). Effects of RYGB on marrow fat differed by diabetes status (adjusted p=0.04). There was little mean change in marrow fat in nondiabetic women (mean +0.9%, 95% CI -10.0 to +11.7%, p=0.84). In contrast, marrow fat decreased in diabetic women (-7.5%, 95% CI -15.2 to +0.1%, p=0.05). Changes in total body fat mass and marrow fat were inversely correlated among nondiabetic (r=-0.96, p=0.01) but not diabetic (r=0.52, p=0.29) participants. In conclusion, among those without diabetes, marrow fat is maintained on average after RYGB, despite dramatic declines in overall fat mass. Among those with diabetes, RYGB may reduce marrow fat. Thus, future studies of marrow fat should take diabetes status into account. Marrow fat may have unique metabolic behavior compared with other fat depots. Copyright © 2015. Published by Elsevier Inc.
    Bone 01/2015; 74. DOI:10.1016/j.bone.2015.01.010 · 4.46 Impact Factor
  • Bone 12/2014; 75. DOI:10.1016/j.bone.2014.11.020 · 4.46 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A bone fractures only when loaded beyond its strength. The purpose of this study was to determine the association of femoral strength, as estimated by finite element (FE) analysis of DXA scans, with incident hip fracture in comparison to hip BMD, FRAX® and hip structure analysis (HSA) variables. This prospective case-cohort study included a random sample of 1941 women and 668 incident hip fracture cases (295 in the random sample) during a mean ± SD follow-up of 12.8 ± 5.7 yrs from the Study of Osteoporotic Fractures (n = 7860 community-dwelling women ≥67 yr of age). We analyzed the baseline DXA scans (Holgoic 1000) of the hip using a validated plane-stress, linear-elastic finite element (FE) model of the proximal femur and estimated the femoral strength during a simulated sideways fall. Cox regression accounting for the case-cohort design assessed the association of estimated femoral strength with hip fracture. The age-BMI-adjusted hazard ratio (HR) per SD decrease for estimated strength (2.21, 95% CI 1.95-2.50) was greater than that for TH BMD (1.86, 95% CI 1.67-2.08; p < 0.05), FN BMD (2.04, 95% CI 1.79-2.32; p > 0.05), FRAX® scores (range 1.32-1.68; p < 0.0005) and many HSA variables (range 1.13-2.43; p < 0.005), and the association was still significant (p < 0.05) after further adjustment for hip BMD or FRAX® scores. The association of estimated strength with incident hip fracture was strong (Harrell's C index 0.770), significantly better than TH BMD (0.759, p < 0.05) and FRAX® scores (0.711-0.743, p < 0.0001) but not FN BMD (0.762, p > 0.05) Similar findings were obtained for intra- and extra-capsular fractures. In conclusion, the estimated femoral strength from FE analysis of DXA scans is an independent predictor and performs at least as well as FN BMD in predicting incident hip fracture in postmenopausal women. © 2014 American Society for Bone and Mineral Research.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 12/2014; 29(12). DOI:10.1002/jbmr.2291 · 6.59 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We describe the methods and reliability of radiographic vertebral fracture assessment in MrOS, a cohort of community dwelling men aged ≥ 65 yrs. Lateral spine radiographs were obtained at Visit 1 (2000-2) and 4.6 years later (Visit 2). Using a workflow tool (SpineAnalyzerTM, Optasia Medical), a physician reader completed semi-quantitative (SQ) scoring. Prior to SQ scoring, technicians performed “triage” to reduce physician reader workload, whereby clearly normal spine images were eliminated from SQ scoring with all levels assumed to be SQ = 0 (no fracture, “triage negative”); spine images with any possible fracture or abnormality were passed to the physician reader as “triage positive” images. Using a quality assurance sample of images (n = 20 participants; 8 with baseline only and 12 with baseline and follow-up images) read multiple times, we calculated intra-reader kappa statistics and percent agreement for SQ scores. A subset of 494 participants’ images were read regardless of triage classification to calculate the specificity and sensitivity of triage. Technically adequate images were available for 5958 of 5994 participants at Visit 1, and 4399 of 4423 participants at Visit 2. Triage identified 3215 (53.9%) participants with radiographs that required further evaluation by the physician reader. For prevalent fractures at Visit 1 (SQ ≥ 1), intra-reader kappa statistics ranged from 0.79-0.92; percent agreement ranged from 96.9%-98.9%; sensitivity of the triage was 96.8% and specificity of triage was 46.3%. In conclusion, SQ scoring had excellent intra-rater reliability in our study. The triage process reduces expert reader workload without hindering the ability to identify vertebral fractures.
    Bone 10/2014; 67. DOI:10.1016/j.bone.2014.06.039 · 4.46 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Context: Data are needed to guide therapeutic decisions about stopping bisphosphonates after an initial treatment period. Objective: To define significant predictors of fracture and quantify fracture incidence in risk factor-defined subgroups of women who discontinue zoledronic acid (ZOL) after 3 years of treatment. To determine if continuing ZOL reduces fracture risk in subgroups. Design: 3 year extension of HORIZON. Setting: Multicenter trial. Participants: 1233 women who previously received 3 ZOL treatments during Core trial. Intervention: Randomization to 3 additional annual ZOL (Z6, n=616) or placebo infusions (Z3P3, n=617). Main Outcomes: Risk of Morphometric vertebral fractures (MorphVertFx) and clinical nonvertebral fractures (NVF). Results: Incidence of MorphVertFx in Z3P3 was predicted by: Femoral Neck (FN) T-score ≤-2.5 [OR 3.3(1.4, 8.0), p=0.008], Total Hip (TH) T-score ≤-2.5 [OR 4.0(1.8, 9.0), p=0.0007], and incident MorphVertFx during Core [OR 4.75(1.4, 16.8), p<0.015]. Incidence of NVF was predicted by TH T-score [for 1 decline, HR 1.7(1.2, 2.6), p=0.008], incident NVF during Core [HR 2.5(1.2, 5.3), p=0.014], and prevalent vertebral fracture [HR 3.0(1.4, 6.3), p=0.005]. For MorphVertFx, there were no significant treatment subgroup interactions; absolute fracture reductions with continued ZOL were greatest in high-risk subgroups. For NVF, there were no significant treatment reductions overall or in subgroups and no significant interactions. Conclusions: After 3 years of ZOL, in women who have a TH T-score above -2.5, no recent incident fracture and no more than one risk factor (almost 55% of the population), risk for subsequent fracture is low if treatment is discontinued (for MorphVertFx average risk 3.2%, range 2.8-3.8% for subgroups, and for NVF average risk 5.8%, range 1.1-8.8% for subgroups). In these patients, discontinuation for up to 3 years is reasonable.
    Journal of Clinical Endocrinology &amp Metabolism 09/2014; DOI:10.1210/jc.2014-1971 · 6.31 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In men, the association between poor physical performance and likelihood of incident vertebral fractures is unknown.Using data from the MrOS study (N=5958), we describe the association between baseline physical performance [walking speed, grip strength, leg power, repeat chair stands, narrow walk (dynamic balance)] and incidence of radiographic and clinical vertebral fractures. At baseline and follow-up an average of 4.6 years later, radiographic vertebral fractures were assessed using semi-quantitative (SQ) scoring on lateral thoracic and lumbar radiographs. Logistic regression modeled the association between physical performance and incident radiographic vertebral fractures (change in SQ grade≥ from baseline to follow-up). Every four months after baseline, participants self-reported fractures; clinical vertebral fractures were confirmed by centralized radiologist review of the baseline study radiograph and community acquired spine images. Proportional hazards regression modeled the association between physical performance with incident clinical vertebral fractures. Multivariate models were adjusted for age, BMD (by DXA), clinical center, race, smoking, height, weight, history of falls, activity level and co-morbid medical conditions; physical performance was analyzed as quartiles.Of 4332 men with baseline and repeat radiographs, 192 (4.4%) had an incident radiographic vertebral fracture. With the exception of walking speed, poorer performance on repeat chair stands, leg power, narrow walk and grip strength were each associated in a graded manner with an increased risk of incident radiographic vertebral fracture (p for trend across quartiles <0.001). In addition, men with performance in the worst quartile on three or more exams had an increased risk of radiographic fracture (OR: 1.81, 9% CI: 1.33, 2.45) compared to men with better performance on all exams. Clinical vertebral fracture (N=149 of 5,813, 2.6%) was not consistently associated with physical performance.We conclude that poorer physical performance is associated with an increased risk of incident radiographic (but not clinical) vertebral fracture in older men. © 2014 American Society for Bone and Mineral Research
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 09/2014; 29(9). DOI:10.1002/jbmr.2239 · 6.59 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Several studies have shown that high bone turnover is associated with 1) greater rates of bone loss and 2) greater BMD response to anti-resorptive therapy in postmenopausal osteoporosis. However, it is not known whether greater rates of bone loss prior to therapy are associated with greater BMD response to anti-resorptive therapy. In the HORIZON-PFT study and its extension, one group of women who were randomized to receive placebo for 3 years (years 1, 2 and 3), were then switched to ZOL 5 mg annually for up to three injections (years 4, 5 and 6, P3Z3 arm) (n = 1223). We measured total hip BMD at baseline, 1, 2 and 3 years on placebo and at 4.5 and 6 years on ZOL. The PINP was measured at 3, 4.5 and 6 years. By design, not all subjects were followed for as long as 6 years, so this analysis focused on the results at 4.5 years. Those with the largest loss in total hip BMD during PBO in years 0-3 had largest gain during ZOL (years 3 to 4.5): (r= -0.39, p < 0.0001). The change in total hip BMD in years 0-3 on placebo was related to the serum PINP at the end of the 3-year period (r= -0.24, P < 0.0001). The change in total hip BMD on ZOL from year 3 to 4.5 was related to the serum PINP at the end of the 3-year period (r= 0.26, P < 0.0001). We conclude that BMD response to ZOL is greater in postmenopausal women who had larger loss prior to treatment. This association may result from higher bone turnover being associated with both greater bone loss on placebo and greater BMD response to ZOL. © 2014 American Society for Bone and Mineral Research
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 09/2014; 30(3). DOI:10.1002/jbmr.2361 · 6.59 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Context: Women stopping alendronate are commonly monitored with serial BMD measurements, yet no information exists on how frequently or for whom these measurements should be performed. Objective: To develop a tool to guide post-alendronate BMD monitoring. Design: A predictive model was constructed to estimate the time until a given percentage of women's BMD T-scores drop below a given threshold where a management change (such as retreatment) would be considered. This model was then used to estimate the time it would take for groups of women defined by their baseline BMDs to drop below the given threshold. Setting: Data were derived from the Fracture Intervention Trial Long Term Extension (FLEX), the largest multi-center clinical trial of its type to date. Participants: Four-hundred and four women who had received an average of 5.1 years of alendronate during the Fracture Intervention Trial and were subsequently followed for 5 treatment-free years (on placebo) during the FLEX trial were used to estimate change in BMD over time. Results: If a management change such as alendronate reinitiation would be considered when BMD T-score drops below -2.5, the model shows that women with total hip BMD greater than -1.9 T-scores at the time of alendronate discontinuation have less than a 20% probability that a follow-up, monitoring BMD will be below the threshold within 5 years. The model performed similarly, and results are provided for a range of management change thresholds from -1.75 to -3 T-scores. Conclusions: Using the tool developed in this analysis, it is possible to estimate when BMD repeat measurement after alendronate discontinuation could be potentially useful. Measuring BMD within 5 years after alendronate discontinuation is unlikely to change management for women with total hip BMD 0.6 T-scores above a pre-specified retreatment threshold within the range of -1.75 to -3 T-scores.
    Journal of Clinical Endocrinology &amp Metabolism 08/2014; DOI:10.1210/jc.2014-1193 · 6.31 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Studies have shown that bisphosphonates may have antitumor and antimetastatic properties. Recently, observational studies have suggested a possible protective effect of bisphosphonates on breast cancer, but the effect of bisphosphonate use on risk of breast cancer has not been tested in randomized trials.
    JAMA Internal Medicine 08/2014; DOI:10.1001/jamainternmed.2014.3634 · 13.25 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: 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 17 beta-estradiol (t-E-2), 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-E-2. 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-E-2. 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.
    Annals of internal medicine 07/2014; 161(4). DOI:10.7326/M14-0353 · 16.10 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    American Journal of Perinatology 06/2014; 32(03). DOI:10.1055/s-0034-1382255 · 1.60 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    Diabetologia 06/2014; 57(10). DOI:10.1007/s00125-014-3289-6 · 6.88 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: IMPORTANCE Discontinuation of bisphosphonate therapy after 3 to 5 years is increasingly considered, but methods to monitor fracture risk after discontinuation have not been established. OBJECTIVE To test methods of predicting fracture risk among women who have discontinued alendronate therapy after 4 to 5 years. DESIGN, SETTING, AND PARTICIPANTS The prospective Fracture Intervention Trial Long-term Extension (FLEX) study randomized postmenopausal women aged 61 to 86 years previously treated with 4 to 5 years of alendronate therapy to 5 more years of alendronate or placebo from 1998 through 2003; the present analysis includes only the placebo group. Hip and spine dual-energy x-ray absorptiometry (DXA) were measured when placebo was begun (FLEX baseline) and after 1 to 3 years of follow-up. Two biochemical markers of bone turnover, urinary type 1 collagen cross-linked N-telopeptide (NTX) and serum bone-specific alkaline phosphatase (BAP), were measured at FLEX baseline and after 1 and 3 years. MAIN OUTCOMES AND MEASURES Symptomatic spine and nonspine fractures occurring after the follow-up measurement of DXA or bone turnover. RESULTS During 5 years of placebo, 94 of 437 women (22%) experienced 1 or more symptomatic fractures; 82 had fractures after 1 year. One-year changes in hip DXA, NTX, and BAP were not related to subsequent fracture risk, but older age and lower hip DXA at time of discontinuation were significantly related to increased fracture risk (lowest tertile of baseline femoral neck DXA vs other 2 tertiles relative hazard ratio, 2.17 [95% CI, 1.38-3.41]; total hip DXA relative hazard ratio, 1.87 [95% CI, 1.20-2.92]). CONCLUSIONS AND RELEVANCE Among postmenopausal women who discontinue alendronate therapy after 4 to 5 years, age and hip BMD at discontinuation predict clinical fractures during the subsequent 5 years. Follow-up measurements of DXA 1 year after discontinuation and of BAP or NTX 1 to 2 years after discontinuation are not associated with fracture risk and cannot be recommended. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00398931.
    JAMA Internal Medicine 05/2014; 174(7). DOI:10.1001/jamainternmed.2014.1232 · 13.25 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A significant link between cardiovascular disease and osteoporosis is established in postmenopausal women, but data in men are scarce. We tested the hypothesis that greater severity of abdominal aortic calcification (AAC) was associated with an increased risk of non-spine fracture in 5994 men aged ≥65 years. AAC wasassessed on 5400 baseline lateral thoraco-lumbar radiographs using a validated visual semi-quantitative score. Total hip bone mineral density (BMD) was measured using dual energy X-ray absorptiometry. Incident non-spine fractures were centrally adjudicated. After adjustment for age, BMI, total hip BMD, fall history, prior fracture, smoking status, co-morbidities, race and clinical center, the risk of non-spine fracture (n = 805) was increased among men with higher AAC (HR Q4 (AAC score ≥9) vs Q1 (0-1): 1.36, 96%CI: 1.10-1.68). This association was due to an increased risk of hip fracture (n = 178) among men with higher AAC (HR Q4 vs Q1: 2.33, 95%CI: 1.41-3.87). By contrast, the association between AAC and the risk of non-spine-non-hip fracture was weaker and not significant (HR Q4 vs Q1: 1.22, 95%CI: 0.96-1.55). The findings regarding higher AAC and increased risk of fracture were not altered in additional analyses accounting for degree of trauma, estimated glomerular filtration rate, presence of lumbar vertebral fractures (which may bias AAC assessment), preexisting cardiovascular disease, ankle brachial index or competing risk of death. Thus, in this large cohort of elderly men, greater AAC was independently associated with an increased risk of hip fracture, but not with other non-spine fractures. These findings suggest that AAC assessment may be a useful method for identification of older men at high risk of hip fracture.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 04/2014; 29(4). DOI:10.1002/jbmr.2085 · 6.59 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Midlife vascular risk factors influence later cognitive decline and Alzheimer's disease (AD). The decrease in serum estradiol levels during menopause has been associated with cognitive impairment and increased vascular risk, such as high blood pressure (BP), which independently contributes to cognitive dysfunction and AD. We describe the extent to which vascular risk factors relate to cognition in healthy, middle-aged, recently postmenopausal women enrolled in the Kronos Early Estrogen Prevention Cognitive and Affective Study (KEEPS-Cog) at baseline. KEEPS-Cog is a double-blind, randomized, placebo-controlled, parallel group, clinical trial, investigating the efficacy of low-dose, transdermal 17β-estradiol and oral conjugated equine estrogen on cognition. All results are cross-sectional and represent baseline data only. Analyses confirm that the KEEPS-Cog cohort (n = 571) was middle aged (mean 52.7 years, range 42-59 years), healthy, and free of cognitive dysfunction. Higher systolic BP was weakly related to poorer performance in auditory working memory and attention (p = 0.004; adjusted for multiple comparisons p = 0.10). This relationship was not associated with endogenous hormone levels, and systolic BP was not related to any other cognitive domain. BP levels may be more sensitive than other vascular risk factors in detecting subtle differences in cognitive task performance in healthy, recently menopausal women. Lower BP early in menopause may affect cognitive domains known to be associated with AD.
    Journal of Alzheimer's disease: JAD 01/2014; 40(2). DOI:10.3233/JAD-130245 · 3.61 Impact Factor

Publication Stats

37k Citations
2,924.12 Total Impact Points

Institutions

  • 1984–2015
    • University of California, San Francisco
      • • Department of Epidemiology and Biostatistics
      • • Division of General Internal Medicine
      • • Division of Prevention Science
      • • Division of Hospital Medicine
      San Francisco, California, United States
  • 2014
    • University of Auckland
      • Department of Medicine
      Окленд, Auckland, New Zealand
  • 1996–2013
    • University of San Francisco
      San Francisco, California, United States
    • CSU Mentor
      • Department of Medicine
      Long Beach, California, United States
  • 2007–2012
    • California Pacific Medical Center Research Institute
      • Research Institute
      San Francisco, California, United States
    • The Chinese University of Hong Kong
      Hong Kong, Hong Kong
    • St. Joseph's Hospital
      Savannah, Georgia, United States
  • 2010
    • United States University
      Chula Vista, California, United States
  • 2009
    • The University of Sheffield
      Sheffield, England, United Kingdom
    • University of Leuven
      Louvain, Flemish, Belgium
  • 1995–2007
    • University of Pittsburgh
      • Department of Epidemiology
      Pittsburgh, Pennsylvania, United States
  • 2004
    • Columbia University
      New York, New York, United States
  • 2002
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
    • Università degli Studi di Siena
      Siena, Tuscany, Italy
  • 2001
    • University of Toronto
      Toronto, Ontario, Canada
    • University of Alabama at Birmingham
      Birmingham, Alabama, United States
  • 2000
    • Minneapolis Veterans Affairs Hospital
      Minneapolis, Minnesota, United States
  • 1999
    • Kaiser Permanente
      Oakland, California, United States
  • 1997
    • Spokane VA Medical Center
      Spokane, Washington, United States
  • 1991
    • San Diego Zoo
      San Diego, California, United States
  • 1989
    • Potomac Institute for Policy Studies
      Arlington, Virginia, United States