Dennis M Black

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

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Publications (275)2774.35 Total impact

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    ABSTRACT: Background: 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. Methods: The association of treatment outcomes with variation in the same 764 candidate genes was evaluated in same KEEPS participants four years after randomization to either oral conjugated equine estrogens (0.45 mg/day), transdermal 17β estradiol (50 µg/day), each with progesterone (200 mg/day) for 12 days each month, or placebo pills and patch. Results: Twenty SNPs within the innate immunity pathway most related with CIMT after 4 years were not among those associated with CIMT prior to MHT. In 403 women who completed the study in their assigned treatment group, SNPs within the innate immunity pathway were found to alter the treatment effect on 4-year 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 years. Conclusion: 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. Key words: atherosclerosis, candidate genes, estrogen, innate immunity, thrombosis.
    Physiological Genomics 10/2015; DOI:10.1152/physiolgenomics.00029.2015 · 2.37 Impact Factor
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    ABSTRACT: 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: NCT01022580.
    The Journal of pediatrics 10/2015; DOI:10.1016/j.jpeds.2015.09.031 · 3.79 Impact Factor
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    ABSTRACT: To examine the degree of trauma in major osteoporotic fractures (MOF) in men vs. women, we used data from 15,698 adults aged ≥65 years enrolled in the Osteoporotic Fractures in Men (MrOS) study (5,994 men) and the Study of Osteoporotic Fractures (SOF) (9,704 women). Participants were contacted tri-annually to ascertain incident fractures, which were confirmed by radiographic reports and coded according to degree of self-reported trauma. Trauma was classified as low (fall from ≤ standing height; fall on stairs, steps or curb; minimal trauma other than fall [coughing, turning over]); moderate (collisions with objects during normal activity without associated fall); or high (fall from > standing height; severe trauma [motor vehicle accident, assault]). MOF included hip, clinical vertebral, wrist and humerus fractures. Mean fracture follow-up was 9.1 years in SOF and 8.7 years in MrOS. 14.6% of the MOF in men vs. 6.3% of the MOF in women were classified as high trauma (p < 0.001); men vs. women more often experienced fractures due to severe trauma as well as due to fall > standing height. High trauma fractures were more significantly common in men vs. women at the hip (p = 0.002) and wrist (p < 0.001), but not at the spine or humerus. Among participants with MOF, the odds ratio of a fracture related to high trauma fracture among men vs. women was 3.12 (95% CI 1.70-5.71) after adjustment for traditional risk factors. Findings were similar in analyses limited to participants with hip fractures (OR 3.34, 95% CI 1.04-10.67) and those with wrist fracture (OR 5.68, 95% CI 2.03-15.85). Among community-dwelling older adults, MOF are more likely to be related to high trauma in men than in women. These findings are not explained by sex differences in conventional risk factors and may reflect a greater propensity among men to engage in risky behavior. 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 07/2015; DOI:10.1002/jbmr.2589 · 6.83 Impact Factor
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    A.H. Gee · G M Treece · C J Tonkin · D M Black · K E S Poole ·
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    ABSTRACT: Within each sex, there is an association between hip fracture risk and the size of the proximal femur, with larger femurs apparently more susceptible to fracture. Here, we investigate whether the thickness and density of the femoral cortex play a role in this association: might larger femurs harbour focal, cortical defects? To answer this question, we used cortical bone mapping to measure the distribution of cortical mass surface density (CMSD, mg/cm(2)) in cohorts of 308 males and 125 females. Principal component analysis of the various femoral surfaces led to a measure of size that is linearly independent from shape. After mapping the data onto a canonical femur surface, we used statistical parametric mapping to identify any regions where CMSD depends on size, allowing for other confounding covariates including shape. Our principal finding was a focal patch on the superior femoral neck, where CMSD is reduced by around 1% for each 1% increase in proximal-distal size (p<0.000005 in the males, p<0.001 in the females). This finding appears to be consistent with models of functional adaptation, and may help with the design of interventional strategies for reducing fracture risk. Copyright © 2015. Published by Elsevier Inc.
    Bone 07/2015; 81. DOI:10.1016/j.bone.2015.06.024 · 3.97 Impact Factor
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    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; 81. DOI:10.1016/j.bone.2015.06.019 · 3.97 Impact Factor
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    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. NCT00154180 and NCT00623311.
    PLoS Medicine 06/2015; 12(6):e1001833. DOI:10.1371/journal.pmed.1001833 · 14.43 Impact Factor
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    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; 30(11). DOI:10.1002/jbmr.2552 · 6.83 Impact Factor
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    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 · 6.83 Impact Factor
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    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; 30(8). DOI:10.1002/jbmr.2467 · 6.83 Impact Factor
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    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 · 3.97 Impact Factor

  • Bone 12/2014; 75. DOI:10.1016/j.bone.2014.11.020 · 3.97 Impact Factor
  • Lang Yang · Lisa Palermo · Dennis M Black · Richard Eastell ·
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    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 · 6.83 Impact Factor
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    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 · 3.97 Impact Factor

  • Archives of Disease in Childhood 10/2014; 99(Suppl 2):A186-A187. DOI:10.1136/archdischild-2014-307384.503 · 2.90 Impact Factor
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    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; 99(12):jc20141971. DOI:10.1210/jc.2014-1971 · 6.21 Impact Factor
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    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 · 6.83 Impact Factor
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    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 · 6.83 Impact Factor
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    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; 99(11):jc20141193. DOI:10.1210/jc.2014-1193 · 6.21 Impact Factor
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    ABSTRACT: Importance Studies have shown that bisphosphonates may have antitumor and antimetastatic properties. Recently, observational studies have suggested a possible protective effect of bisphosphonates on breast cancer, but the effect of bisphosphonate use on risk of breast cancer has not been tested in randomized trials.Objective To assess the relationship of postmenopausal breast cancer incidence and bisphosphonate use using data from 2 randomized (1:1), double-blind, placebo-controlled trials.Design, Setting, and Participants The Fracture Intervention Trial (FIT) randomly assigned 6459 women aged 55 to 81 years to alendronate or placebo for a mean follow-up of 3.8 years. The Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly–Pivotal Fracture Trial (HORIZON-PFT) randomly assigned 7765 women aged 65 to 89 years to annual intravenous zoledronic acid or placebo for a mean follow-up of 2.8 years. Data were collected at clinical centers in the United States (FIT and HORIZON-PFT) and in Asia and the Pacific, Europe, North America, and South America (HORIZON-PFT). Women, in either study, with recurrent breast cancer or who reported a history of breast cancer were excluded from analyses. In each trial, a blinded review was conducted of each cancer adverse event report to verify incident invasive breast cancer cases. The primary analysis compared events in the active vs placebo group using a log-rank test.Intervention Alendronate vs placebo (FIT) or zoledronic acid vs placebo (HORIZON-PFT).Main Outcomes and Measures Hazard ratio for incident breast cancer in the bisphosphonate treatment group compared to the placebo group.Results There was no significant difference in the rate of breast cancer in FIT: 1.5% (n = 46) in the placebo group and 1.8% (n = 57) in the alendronate group (hazard ratio [HR], 1.24 [95% CI, 0.84-1.83]). In HORIZON-PFT, there was also no significant difference: 0.8% (n = 29) in the placebo group and 0.9% (n = 33) in the zoledronic acid group (HR, 1.15 [95% CI, 0.70-1.89]). There was also no significant difference when the data from FIT and HORIZON-PFT were pooled (HR, 1.20 [95% CI, 0.89-1.63]).Conclusions and Relevance These 2 randomized clinical trials do not support the findings from observational research. Contrary to the results from observational studies, we found that 3 to 4 years of bisphosphonate treatment did not decrease the risk of invasive postmenopausal breast cancer.Trial Registration Identifier: NCT00049829 (HORIZON-PFT).
    JAMA Internal Medicine 08/2014; 174(10). DOI:10.1001/jamainternmed.2014.3634 · 13.12 Impact Factor
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    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. ( 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 · 17.81 Impact Factor

Publication Stats

36k Citations
2,774.35 Total Impact Points


  • 1984-2015
    • University of California, San Francisco
      • • Department of Epidemiology and Biostatistics
      • • Division of General Internal Medicine
      • • Division of Prevention Science
      • • Department of Medicine
      San Francisco, California, United States
  • 2014
    • University of Auckland
      • Department of Medicine
      Окленд, Auckland, New Zealand
  • 2013
    • University of San Francisco
      San Francisco, 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
  • 2009
    • University of Leuven
      Louvain, Flemish, Belgium
  • 1995-2009
    • University of Pittsburgh
      • • Department of Epidemiology
      • • Graduate School of Public Health
      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
  • 2000
    • Minneapolis Veterans Affairs Hospital
      Minneapolis, Minnesota, United States
  • 1999
    • Kaiser Permanente
      Oakland, California, United States
  • 1997
    • Children's Hospital & Research Center Oakland
      Oakland, California, United States
    • Spokane VA Medical Center
      Spokane, Washington, United States
  • 1996
    • CSU Mentor
      • Department of Medicine
      Long Beach, California, United States
  • 1989
    • Potomac Institute for Policy Studies
      Arlington, Virginia, United States