Dennis M Black

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

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Publications (275)2290.03 Total impact

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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.
    The Journal of clinical endocrinology and metabolism. 08/2014;
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    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; · 10.58 Impact Factor
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    ABSTRACT: Whether menopausal hormone therapy (MHT) protects against cardiovascular disease (CVD) remains unclear.
    Annals of internal medicine 07/2014; · 13.98 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 07/2014; · 6.04 Impact Factor
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    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; · 1.57 Impact Factor
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    ABSTRACT: 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.
    Diabetologia 06/2014; · 6.49 Impact Factor
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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 06/2014; · 6.04 Impact Factor
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    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 Identifier: NCT00398931.
    JAMA Internal Medicine 05/2014; · 10.58 Impact Factor
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    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; · 4.17 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 01/2014; · 3.82 Impact Factor
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    ABSTRACT: AimsTo investigate whether 25-hydroxyvitamin D concentration was associated with incident diabetes in a large cohort of older women. Methods Data were analysed from women included in the Study of Osteoporotic Fractures, a cohort of community-dwelling women aged ≥65 years at enrolment. Serum 25-hydroxyvitamin D concentration was assessed at the year 6 visit, as were BMI and other factors associated with vitamin D and/or diabetes. Diabetes status was determined at each subsequent visit by self-report and medication use. Only those without prevalent diabetes at the year 6 visit were included in the present analysis (N=5463, mean age 76.5 years). ResultsDuring a mean ±sd follow-up of 8.6 ± 4.4 years, incident diabetes was reported in 320 participants. The mean BMI was higher in those with a 25-hydroxyvitamin D concentration <20 ng/ml (<50 nmol/l) than in those with concentrations 20–30 or ≥30 ng/ml [50–74 or ≥75 nmol/l (P<0.0001)]. A higher 25-hydroxyvitamin D concentration was associated with a 13% lower risk of incident diabetes after adjustment for age and clinic site [hazard ratio 0.87, 95% CI 0.76–0.99, per sd increase in 25-hydroxyvitamin D]; however, the addition of BMI to the model attenuated the estimated effect (hazard ratio 0.97, 95% CI 0.86–1.11). Adjustment for additional potential confounders yielded similar results. Conclusions Serum 25-hydroxyvitamin D does not independently predict incident diabetes in older women. Although those with higher 25-hydroxyvitamin D concentrations are less likely to develop diabetes, this is mainly explained by their lower BMI.This article is protected by copyright. All rights reserved.
    Diabetic Medicine 12/2013; · 3.24 Impact Factor
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    Dennis M Black, Anne L Schafer
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    ABSTRACT: Large increases in BMD and reductions in fracture risk, particularly vertebral fractures, have generated much enthusiasm for anabolic therapy in the osteoporosis community. Two forms of PTH [PTH(1-34) or teriparatide, and PTH(1-84)] have been used clinically for almost a decade [PTH(1-84) not in the US] and have been shown to be safe and effective in increasing BMD and reducing fracture risk. However, PTH increases bone resorption as well as formation, and an ideal anabolic treatment would be one that could optimize the impact on formation while producing lesser changes in resorption.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 09/2013; · 6.04 Impact Factor
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    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 08/2013; · 6.04 Impact Factor
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    ABSTRACT: In postmenopausal women receiving combination parathyroid hormone (PTH) (1-84) therapy and ibandronate, we evaluated bone microarchitecture and biomechanics using high-resolution peripheral quantitative computed tomography (HR-pQCT). Cortical and trabecular changes were different at the nonweight-bearing radius vs. the weight-bearing tibia, with more favorable overall changes at the tibia. INTRODUCTION: PTH therapy and bisphosphonates decrease fracture risk in postmenopausal osteoporosis, but their effects on bone microstructure and strength have not been fully characterized, particularly during combination therapy. PTH increases trabecular bone mineral density (BMD) substantially but may decrease cortical BMD, possibly by stimulating intracortical remodeling. We evaluated bone microarchitecture and biomechanics with HR-pQCT at the radius (a nonweight-bearing site) and tibia (weight bearing) in women receiving combination PTH(1-84) and ibandronate. METHODS: Postmenopausal women with low bone mass (n = 43) were treated with 6 months of PTH(1-84) (100 μg/day), either as one 6- or two 3-month courses, in combination with ibandronate (150 mg/month) over 2 years. HR-pQCT was performed before and after therapy. RESULTS: Because changes in HR-pQCT parameters did not differ between treatment arms, groups were pooled into one cohort for analysis. Trabecular BMD increased at both radius and tibia (p < 0.01 for each). Cortical thickness and BMD decreased at the radius (p < 0.01), consistent with changes in dual-energy X-ray absorptiometry, while these parameters did not change at the tibia (p ≤ 0.02 for difference between radius and tibia). In contrast, cortical porosity increased at the tibia (p < 0.01) but not radius. Stiffness and failure load decreased at the radius (p < 0.0001) but did not change at the tibia. CONCLUSIONS: Cortical and trabecular changes in response to the PTH/ibandronate treatment combinations utilized in this study were different at the nonweight-bearing radius vs. the weight-bearing tibia, with more favorable overall changes at the tibia. Our findings support the possibility that weight bearing may optimize the effects of osteoporosis therapy.
    Osteoporosis International 04/2013; · 4.04 Impact Factor
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    ABSTRACT: Management of women discontinuing bisphosphonates after 3-5 years of treatment is controversial. Little is known about how much bone mineral density (BMD) is lost after discontinuation, or whether there are risk factors for greater rates of bone loss post-discontinuation. We report patterns of change in BMD and prediction models for the changes in BMD in postmenopausal women during a 5-year treatment-free period following alendronate (ALN) therapy. We studied 406 women enrolled in the Fracture Intervention Trial (FIT) who had taken ALN for a mean of 5 years and were then enrolled in the placebo arm of the FIT Long Term Extension (FLEX) trial for an additional 5 years, describing 5-year percent changes in total hip, femoral neck, and lumbar spine BMD over the treatment-free period. Prediction models of 5-year percent changes in BMD considered all linear combinations of candidate risk factors for bone loss such as BMD at the start of the treatment-free period, the change in BMD on ALN, age, and fracture history. Serum for three markers of bone turnover was available in 76 women, and these bone turnover markers were included as candidate predictors for these 76 women. Mean 5-year BMD changes were -3.6% at the total hip, -1.7% at the femoral neck, and 1.3% at the lumbar spine. Five-year BMD losses of > 5% were experienced by 29% of subjects at the total hip, 11% of subjects at the femoral neck, and 1% of subjects at the lumbar spine. Several risk factors such as age and BMI were associated with greater bone loss, but no models based on these risk factors predicted bone loss rates. Though about a third of women who discontinue ALN after 5 years experienced > 5% bone loss at the total hip, predicting which women will lose at a higher rate was not possible. © 2013 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 02/2013; · 6.04 Impact Factor
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    ABSTRACT: Context:Patients on long-term bisphosphonate therapy may have an increased incidence of low-energy subtrochanteric and diaphyseal (SD) femoral fractures. However, the incidence and risk factors associated with these fractures have not been well defined.Objective:The objective of the study was to determine the incidence of and risk factors for low-energy SD fractures in the Study of Osteoporotic Fractures (SOF).Design:Low-energy SD fractures were identified from a review of radiographic reports obtained between 1986 and 2010 in women in the SOF. Among the SD fractures, pathological, periprosthetic, and traumatic fractures were excluded. We assessed risk factors for SD fractures as well as risk factors for femoral neck (FN) and intertrochanteric (IT) hip fractures using both age-adjusted and multivariate time-dependent proportional hazards models. During this follow-up, only a small minority had ever used bisphosphonates.Results:Forty-five women sustained low-energy subtrochanteric/diaphyseal femoral fractures over a total follow-up of 140 000 person-years. The incidence of SD fracture was 3.2 per 10 000 person-years compared with a total hip fracture incidence of 110 per 10 000 person-years. A total of about 12% of women reported bisphosphonate use at 1 or more visits. In multivariate analyses, age, total hip bone mineral density (BMD), bisphosphonate use, and history of diabetes emerged as independent risk factors for SD fractures. Risk factors for FN and IT fractures included age, BMD, and history of falls or prior fractures. Bisphosphonate use was protective against FN fractures, whereas there was an increased risk of SD fractures (hazard ratio 2.58, P = .049) with bisphosphonate use after adjustment for other risk factors for fracture.Conclusions:In SOF, low-energy SD fractures were rare occurrences, far outnumbered by FN and IT fractures. Typical risk factors were associated with FN and IT fractures, whereas only age, total hip BMD, and history of diabetes were independent risk factors for SD fractures. In addition, bisphosphonate use was a marginally significantly predictor although the SOF study has limited ability to assess this association.
    The Journal of clinical endocrinology and metabolism 01/2013; · 6.50 Impact Factor
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    ABSTRACT: In rodent models undercarboxylated osteocalcin (ucOC) acts as a hormone promoting insulin sensitivity and secretion. If ucOC plays a similar role in humans, then antiresorptive therapies, which reduce ucOC levels, may increase the risk of insulin resistance and diabetes. We tested whether antiresorptive therapies result in higher fasting glucose, increased weight, or greater diabetes incidence in post-hoc analyses of three randomized, placebo-controlled trials in postmenopausal women: Fracture Intervention Trial (FIT) (N=6151) of alendronate (4 years), Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial (HORIZON-PFT) (N=7113) of zoledronic acid (3 years), and Fracture REduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial (N=7076) of denosumab (3 years). Fasting glucose was measured annually in FIT and HORIZON in a subset of women, and every 6 months in FREEDOM on all participants. Weight was measured annually in all trials. Incident diabetes was identified from adverse event reports, initiation of diabetes medication, or elevated fasting glucose. Differences in fasting glucose changes from randomization to trial conclusion between treatment and placebo groups were not statistically significant: -0.47 mg/dL in FIT, 0.20 mg/dL in HORIZON-PFT and 0.09 mg/dL in FREEDOM, all p>0.6. Weight change differed between treatment and placebo groups in FIT (0.32 kg, p=0.003) and FREEDOM (0.31 kg, p=0.023), but not in HORIZON-PFT (0.15 kg, p=0.132). In the three trials combined, diabetes occurred in 203 and 225 women assigned to treatment or placebo, respectively. Diabetes incidence was not increased in any of the treatment groups or in the pooled estimate (Pooled RR = 0.90; 95% CI 0.74, 1.10). Antiresorptive therapy does not have a clinically important effect on fasting glucose, weight or diabetes risk in postmenopausal women. Contrary to predictions from mouse models, reduced bone turnover does not appear to play a significant role in glucose metabolism in humans. © 2013 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 01/2013; · 6.04 Impact Factor
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    ABSTRACT: Context:Annual infusions of zoledronic acid 5 mg over 3 years have been shown to reduce fracture incidence. There is now evidence that the effects of a single dose of zoledronic acid on bone mineral density and bone turnover last for much more than a year. Whether this is associated with sustained fracture prevention is not known.Objective:The objective of the study was to assess fracture incidence after only 1 infusion of zoledronic acid.Design:The design of the study included post hoc analysis of subgroups of subjects from 2 trials, who received only 1 study infusion.Setting:The study included multicenter, randomized controlled trials.Participants:A total of 1367 subjects from HORIZON-PFT and HORIZON-RFT studies who received only 1 of the planned annual infusions participated in the study.Intervention:The intervention of the study consisted of 1 infusion of zoledronic acid or placebo.Main Outcome Measure:Clinical fracture was the main outcome measure of the study.Results:Mean follow-up period was 1.5 years. In patients who received only a single infusion, there was a 32% reduction in clinical fracture comparing zoledronic acid with placebo over 3 years of follow-up (95% confidence interval 2-53%, P = .04), comparable with the fracture reduction seen in those who had 3 or more annual infusions (34%; 95% confidence interval, 23-43%, P < .0001). New morphometric vertebral fractures were reduced by 68% in the single-infusion group (P = .004). The between-group differences in total hip bone mineral density at 3 years were 3.8% in those receiving 1 infusion and 6.2% in those receiving 3 infusions.Conclusions:In this post hoc analysis based on postrandomization subgroups, fracture risk appears to be reduced for more than 1 year after a single infusion of zoledronic acid. Prospective studies designed to assess this possibility are now warranted.
    The Journal of clinical endocrinology and metabolism 01/2013; · 6.50 Impact Factor
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    ABSTRACT: OBJECTIVE: To determine whether self-reported menopausal symptoms are associated with measures of subclinical atherosclerosis. DESIGN: Cross-sectional analysis. SETTING: Multicenter, randomized controlled trial. PATIENT(S): Recently menopausal women (n = 868) screened for the Kronos Early Estrogen Prevention Study (KEEPS). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Baseline menopausal symptoms (hot flashes, dyspareunia, vaginal dryness, night sweats, palpitations, mood swings, depression, insomnia, irritability), serum E(2) levels, and measures of atherosclerosis were assessed. Atherosclerosis was quantified using coronary artery calcium (CAC) Agatston scores (n = 771) and carotid intima-media thickness (CIMT). Logistic regression model of menopausal symptoms and E(2) was used to predict CAC. Linear regression model of menopausal symptoms and E(2) was used to predict CIMT. Correlation between length of time in menopause with menopausal symptoms, E(2), CAC, and CIMT were assessed. RESULT(S): In early menopausal women screened for KEEPS, neither E(2) nor climacteric symptoms predicted the extent of subclinical atherosclerosis. Palpitations and depression approached significance as predictors of CAC. Other symptoms of insomnia, irritability, dyspareunia, hot flashes, mood swings, night sweats, and vaginal dryness were not associated with CAC. Women with significantly elevated CAC scores were excluded from further participation in KEEPS; in women meeting inclusion criteria, neither baseline menopausal symptoms nor E(2) predicted CIMT. Years since menopause onset correlated with CIMT, dyspareunia, vaginal dryness, and E(2). CONCLUSION(S): Self-reported symptoms in recently menopausal women are not strong predictors of subclinical atherosclerosis. Continued follow-up of this population will be performed to determine whether baseline or persistent symptoms in the early menopause are associated with progression of cardiovascular disease. CLINICAL TRIAL REGISTRATION NUMBER: NCT00154180.
    Fertility and sterility 01/2013; 99(5):1384-91. · 3.97 Impact Factor
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    ABSTRACT: Older women with type 2 diabetes mellitus (DM) have higher bone mineral density (BMD) but also have higher rates of fracture compared to those without DM. Limited evidence suggests that DM may also be associated with more rapid bone loss. To determine if bone loss rates differ by DM status in older women, we analyzed BMD data in the Study of Osteoporotic Fractures (SOF) between 1986 and 1998. SOF participants were women ≥65 years at baseline who were recruited from four regions in the U.S. DM was ascertained by self-report. BMD was measured with dual-energy x-ray absorptiometry (DXA) at baseline and at least one follow-up visit at the hip (N = 6624) and calcaneus (N = 6700) and, on a subset of women, at the spine (N = 396) and distal radius (N = 306). Annualized percent change in BMD was compared by DM status, using random effects models. Of 6,867 women with at least one follow-up DXA scan, 409 had DM at baseline. Mean age was 70.8 (SD 4.7) years. Baseline BMD was higher in women with DM at all measured sites. In models adjusted for age and clinic, women with prevalent DM lost bone more rapidly than those without DM at the femoral neck (-0.96 vs. -0.59%/year, p < 0.001), total hip (-0.98 vs. -0.70%/year, p < 0.001), calcaneus (-1.64 vs. -1.40%/year, p = 0.005), and spine (-0.33 vs. +0.33%/year, p = 0.033), but not at the distal radius (-0.97 vs. -0.90%/year, p = 0.91). These findings suggest that despite higher baseline BMD, older women with DM experience more rapid bone loss than those without DM at the hip, spine, and calcaneus, but not the radius. Higher rates of bone loss may partially explain higher fracture rates in older women with DM.
    Frontiers in Endocrinology 01/2013; 4:62.

Publication Stats

29k Citations
2,290.03 Total Impact Points


  • 1988–2014
    • University of California, San Francisco
      • • Department of Epidemiology and Biostatistics
      • • Division of Hospital Medicine
      • • Division of General Internal Medicine
      San Francisco, California, United States
  • 2013
    • San Francisco VA Medical Center
      San Francisco, California, United States
    • University of Minnesota Duluth
      Duluth, Minnesota, United States
  • 2009–2013
    • University of Lyon
      Lyons, Rhône-Alpes, France
    • Harvard Medical School
      Boston, Massachusetts, United States
    • Case Western Reserve University
      • Department of Pediatrics (University Hospitals Case Medical Center)
      Cleveland, OH, United States
    • Sheffield Teaching Hospitals NHS Foundation Trust
      Sheffield, England, United Kingdom
  • 2000–2013
    • Minneapolis Veterans Affairs Hospital
      Minneapolis, Minnesota, United States
  • 1996–2013
    • University of San Francisco
      San Francisco, California, United States
  • 2012
    • University of Leuven
      Louvain, Flanders, Belgium
    • University of Florence
      • Dipartimento di Medicina Sperimentale e Clinica
      Florence, Tuscany, Italy
  • 2007–2012
    • The University of Sheffield
      • School of Health and Related Research (ScHARR)
      Sheffield, ENG, United Kingdom
    • St. Joseph's Hospital
      Savannah, Georgia, United States
  • 2007–2011
    • California Pacific Medical Center Research Institute
      • Research Institute
      San Francisco, California, United States
  • 1992–2011
    • Kaiser Permanente
      • Center for Health Research (Oregon, Hawaii, and Georgia)
      Oakland, California, United States
  • 2010
    • University of Alabama at Birmingham
      • Division of Clinical Immunology and Rheumatology
      Birmingham, AL, United States
  • 2005–2010
    • University of Auckland
      • Department of Medicine
      Auckland, Auckland, New Zealand
    • U.S. Department of Veterans Affairs
      • Geriatric Research, Education and Clinical Center (GRECC)
      Washington, Washington, D.C., United States
    • Wake Forest School of Medicine
      • Division of Public Health Sciences
      Winston-Salem, NC, United States
  • 2008
    • University of California, Berkeley
      • Department of Mechanical Engineering
      Berkeley, CA, United States
  • 1996–2008
    • CSU Mentor
      • Department of Medicine
      Long Beach, California, United States
  • 1995–2008
    • University of Pittsburgh
      • Department of Epidemiology
      Pittsburgh, PA, United States
  • 2006
    • University of Toronto
      • Department of Medicine
      Toronto, Ontario, Canada
  • 2004
    • University of Minnesota Twin Cities
      • Department of Medicine
      Minneapolis, Minnesota, United States
  • 2003
    • Malmö University
      Malmö, Skåne, Sweden
  • 2002
    • Claude Bernard University Lyon 1
      Villeurbanne, Rhône-Alpes, France
    • Brigham and Women's Hospital
      • Department of Medicine
      Boston, MA, United States
    • Beth Israel Deaconess Medical Center
      Boston, Massachusetts, United States
  • 2001
    • University of Iowa
      • Department of Epidemiology
      Iowa City, IA, United States