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A. Ishani,
M. Paudel,
B. C. Taylor,
E. Barrett-Connor,
S. Jamal,
M. Canales,
M. Steffes,
H. A. Fink,
E. Orwoll, S. R. Cummings,
K. E. Ensrud,
for the Osteoporotic Fractures in Men (MrOS) Study Group
[show abstract]
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ABSTRACT: SummaryOlder men with reduced renal function are at increased risk of hip bone loss. Given the robustness of this association across
different measures and a growing body of literature, our findings indicate that clinicians should take into account renal
function when evaluating older men for osteoporosis risk and bone loss. Future randomized controlled trials should test whether
interventions in this high risk population are effective in preventing bone loss and decreasing fracture incidence.
IntroductionStudies examining whether kidney impairment, not requiring dialysis, is associated with osteoporosis have reported conflicting
results.
MethodsWe tested the hypothesis that reduced renal function in older men as manifested by higher concentrations of cystatin C or
lower levels of estimated glomerular filtration rate (eGFR) is associated with higher rates of bone loss. We measured serum
cystatin C, serum creatinine and total hip bone mineral density (BMD) at baseline in a cohort of 404 older men enrolled in
the Osteoporotic Fractures in Men (MrOS) Study and followed them prospectively for an average of 4.4years for changes in
BMD. Associations between renal function and change in hip BMD were examined using linear regression.
ResultsIn multivariable analysis, the mean rate of decline in total hip BMD showed an increase in magnitude with higher cystatin
C concentration (mean annualized percent change −0.29, −0.34, −0.37 and −0.65% for quartiles 1 to 4; p for trend=0.004). Similarly,
adjusted rates of hip bone loss were higher among men with lower eGFR as defined by the modification of diet in renal disease
formula (mean annualized percent change −0.58, −0.39, −0.37, and −0.31 for quartiles 1 to 4; p for trend=0.02), but not among
men with lower eGFR as defined by the Cockcroft–Gault formula (mean annualized percent change −0.47, −0.44, −0.31 and −0.43
for quartiles 1 to 4; p for trend=0.48).
ConclusionsOlder men with reduced renal function are at increased risk of hip bone loss. Our findings suggest that health care providers
should consider renal function when evaluating older men for risk factors for bone loss and osteoporosis.
Osteoporosis International 04/2012; 19(11):1549-1556. · 4.58 Impact Factor
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[show abstract]
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ABSTRACT: We used a microsimulation model to estimate the threshold body weights at which screening bone densitometry is cost-effective. Among women aged 55-65 years and men aged 55-75 years without a prior fracture, body weight can be used to identify those for whom bone densitometry is cost-effective. INTRODUCTION: Bone densitometry may be more cost-effective for those with lower body weight since the prevalence of osteoporosis is higher for those with low body weight. Our purpose was to estimate weight thresholds below which bone densitometry is cost-effective for women and men without a prior clinical fracture at ages 55, 60, 65, 75, and 80 years. METHODS: We used a microsimulation model to estimate the costs and health benefits of bone densitometry and 5 years of fracture prevention therapy for those without prior fracture but with femoral neck osteoporosis (T-score ≤ -2.5) and a 10-year hip fracture risk of ≥3%. Threshold pre-test probabilities of low BMD warranting drug therapy at which bone densitometry is cost-effective were calculated. Corresponding body weight thresholds were estimated using data from the Study of Osteoporotic Fractures (SOF), the Osteoporotic Fractures in Men (MrOS) study, and the National Health and Nutrition Examination Survey (NHANES) for 2005-2006. RESULTS: Assuming a willingness to pay of $75,000 per quality adjusted life year (QALY) and drug cost of $500/year, body weight thresholds below which bone densitometry is cost-effective for those without a prior fracture were 74, 90, and 100 kg, respectively, for women aged 55, 65, and 80 years; and were 67, 101, and 108 kg, respectively, for men aged 55, 75, and 80 years. CONCLUSIONS: For women aged 55-65 years and men aged 55-75 years without a prior fracture, body weight can be used to select those for whom bone densitometry is cost-effective.
Osteoporosis International 02/2012; · 4.58 Impact Factor
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Dennis M Black,
Ian R Reid,
Steven Boonen,
Christina Bucci-Rechtweg,
Jane A Cauley,
Felicia Cosman, Steven R Cummings,
Trisha F Hue,
Kurt Lippuner,
Peter Lakatos,
Ping Chung Leung,
Zulema Man,
Ruvie Lou Maria Martinez,
Monique Tan,
Mary Ellen Ruzycky,
Guoqin Su,
Richard Eastell
[show abstract]
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ABSTRACT: Zoledronic acid 5 mg (ZOL) annually for 3 years reduces fracture risk in postmenopausal women with osteoporosis. To investigate long-term effects of ZOL on bone mineral density (BMD) and fracture risk, the Health Outcomes and Reduced Incidence with Zoledronic acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT) was extended to 6 years. In this international, multicenter, double-blind, placebo-controlled extension trial, 1233 postmenopausal women who received ZOL for 3 years in the core study were randomized to 3 additional years of ZOL (Z6, n = 616) or placebo (Z3P3, n = 617). The primary endpoint was femoral neck (FN) BMD percentage change from year 3 to 6 in the intent-to-treat (ITT) population. Secondary endpoints included other BMD sites, fractures, biochemical bone turnover markers, and safety. In years 3 to 6, FN-BMD remained constant in Z6 and dropped slightly in Z3P3 (between-treatment difference = 1.04%; 95% confidence interval 0.4 to 1.7; p = 0.0009) but remained above pretreatment levels. Other BMD sites showed similar differences. Biochemical markers remained constant in Z6 but rose slightly in Z3P3, remaining well below pretreatment levels in both. New morphometric vertebral fractures were lower in the Z6 (n = 14) versus Z3P3 (n = 30) group (odds ratio = 0.51; p = 0.035), whereas other fractures were not different. Significantly more Z6 patients had a transient increase in serum creatinine >0.5 mg/dL (0.65% versus 2.94% in Z3P3). Nonsignificant increases in Z6 of atrial fibrillation serious adverse events (2.0% versus 1.1% in Z3P3; p = 0.26) and stroke (3.1% versus 1.5% in Z3P3; p = 0.06) were seen. Postdose symptoms were similar in both groups. Reports of hypertension were significantly lower in Z6 versus Z3P3 (7.8% versus 15.1%, p < 0.001). Small differences in bone density and markers in those who continued versus those who stopped treatment suggest residual effects, and therefore, after 3 years of annual ZOL, many patients may discontinue therapy up to 3 years. However, vertebral fracture reductions suggest that those at high fracture risk, particularly vertebral fracture, may benefit by continued treatment.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 12/2011; 27(2):243-54. · 6.04 Impact Factor
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ABSTRACT: Objective:Obesity and shorter telomeres are commonly associated with elevated risk for age-related diseases and mortality. Whether telomere length (TL) may be associated with obesity or variations in adiposity is not well established. Therefore, we set out to test the hypothesis that TL may be a risk factor for increased adiposity using data from a large population-based cohort study.Design:Levels of adiposity were assessed in six ways (obesity status, body mass index (BMI), the percentage of body fat or % body fat, leptin, visceral and subcutaneous fat mass) in 2721 elderly subjects (42% black and 58% white). Associations between TL measured in leukocytes at baseline and adiposity traits measured at baseline, and three of these traits after 7 years of follow-up were tested using regression models adjusting for important covariates. Additionally, we look at weight changes and relative changes in BMI and % body fat between baseline and follow-up.Results:At baseline, TL was negatively associated with % body fat (ß=-0.35±0.09, P=0.001) and subcutaneous fat (ß=-2.66±1.07, P=0.01), and positively associated with leptin after adjusting for % body fat (ß=0.32±0.14, P=0.001), but not with obesity, BMI or visceral fat. Prospective analyses showed that longer TL was associated with positive percent change between baseline and 7-year follow-up for both BMI (ß=0.48±0.20, P=0.01) and % body fat (ß=0.42±0.23, P=0.05).Conclusion:Our study suggests that shorter TL may be a risk factor for increased adiposity. Coupling with previous reports on their reversed roles, the relationship between adiposity and TL may be complicated and may warrant more prospective studies.
International journal of obesity (2005) 10/2011; 36(9):1176-9. · 4.34 Impact Factor
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S Boonen,
J D Adachi,
Z Man, S R Cummings,
K Lippuner,
O Törring,
J C Gallagher,
J Farrerons,
A Wang,
N Franchimont,
J San Martin,
A Grauer,
M McClung
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ABSTRACT: The FREEDOM (Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months) trial showed denosumab significantly reduced the risk of fractures in postmenopausal women with osteoporosis.
We evaluated the effect of denosumab on the incidence of new vertebral and hip fractures in subgroups of women at higher risk for these fractures.
FREEDOM was a 3-yr, randomized, double-blind, placebo-controlled, phase 3 trial.
Postmenopausal women (N = 7808) with osteoporosis were enrolled at 213 study sites worldwide.
Subjects received s.c. denosumab (60 mg) or placebo every 6 months and daily supplements of calcium (≥1000 mg) and vitamin D (≥400 IU).
This post hoc analysis evaluated fracture incidence in women with known risk factors for fractures including multiple and/or moderate or severe prevalent vertebral fractures, aged 75 yr or older, and/or femoral neck bone mineral density T-score of -2.5 or less.
Compared with placebo, denosumab significantly reduced the risk of new vertebral fractures in women with multiple and/or severe prevalent vertebral fractures (16.6% placebo vs. 7.5% denosumab; P < 0.001). Similarly, denosumab significantly reduced the risk of hip fractures in subjects aged 75 yr or older (2.3% placebo vs. 0.9% denosumab; P < 0.01) or with a baseline femoral neck bone mineral density T-score of -2.5 or less (2.8% placebo vs. 1.4% denosumab; P = 0.02). These risk reductions in higher-risk individuals were consistent with those seen in patients at lower risk of fracture.
Denosumab reduced the incidence of new vertebral and hip fractures in postmenopausal women with osteoporosis at higher risk for fracture. These results highlight the consistent antifracture efficacy of denosumab in patients with varying degrees of fracture risk.
The Journal of clinical endocrinology and metabolism 03/2011; 96(6):1727-36. · 6.50 Impact Factor
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Meghan G Donaldson,
Peggy M Cawthon,
John T Schousboe,
Kristine E Ensrud,
Li-Yung Lui,
Jane A Cauley,
Teresa A Hillier,
Brent C Taylor,
Marc C Hochberg,
Douglas C Bauer, Steven R Cummings
[show abstract]
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ABSTRACT: Fracture prediction models help to identify individuals at high risk who may benefit from treatment. Area under the curve (AUC) is used to compare prediction models. However, the AUC has limitations and may miss important differences between models. Novel reclassification methods quantify how accurately models classify patients who benefit from treatment and the proportion of patients above/below treatment thresholds. We applied two reclassification methods, using the National Osteoporosis Foundation (NOF) treatment thresholds, to compare two risk models: femoral neck bone mineral density (BMD) and age (simple model) and FRAX (FRAX model). The Pepe method classifies based on case/noncase status and examines the proportion of each above and below thresholds. The Cook method examines fracture rates above and below thresholds. We applied these to the Study of Osteoporotic Fractures (SOF). There were 6036 (1037 fractures) and 6232 (389 fractures) participants with complete data for major osteoporotic and hip fracture, respectively. Both models for major osteoporotic fracture (0.68 versus 0.69) and hip fracture (0.75 versus 0.76) had similar AUCs. In contrast, using reclassification methods, each model classified a substantial number of women differently. Using the Pepe method, the FRAX model (versus the simple model) missed treating 70 (7%) cases of major osteoporotic fracture but avoided treating 285 (6%) noncases. For hip fracture, the FRAX model missed treating 31 (8%) cases but avoided treating 1026 (18%) noncases. The Cook method (both models, both fracture outcomes) had similar fracture rates above/below the treatment thresholds. Compared with the AUC, new methods provide more detailed information about how models classify patients.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 02/2011; 26(8):1767-73. · 6.04 Impact Factor
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Meghan G Donaldson,
Peggy M Cawthon,
Lily Y Lui,
John T Schousboe,
Kristine E Ensrud,
Brent C Taylor,
Jane A Cauley,
Teresa A Hillier,
Thuy T Dam,
Jeff R Curtis,
Dennis M Black,
Douglas C Bauer,
Eric S Orwoll, Steven R Cummings
[show abstract]
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ABSTRACT: The new US National Osteoporosis Foundation's (NOF's) Clinician's Guide to Prevention and Treatment of Osteoporosis includes criteria for recommending pharmacologic treatment based on history of hip or vertebral fracture, femoral neck or spine bone mineral density (BMD) T-scores of -2.5 or less, and presence of low bone mass at the femoral neck or spine plus a 10-year risk of hip fracture of 3% or greater or of major osteoporotic fracture of 20% or greater. The proportion of men who would be recommended for treatment by these guidelines is not known. We applied the NOF criteria for treatment to men participating in the Osteoporotic Fractures in Men Study (MrOS). To determine how the MrOS population differs from the general US population of Caucasian men aged 65 years and older, we compared men in MrOS with men who participated in the National Health and Nutrition Examination Survey (NHANES) III on criteria included in the NOF treatment guidelines that were common to both cohorts. Compared with NHANES III, men in MrOS had higher femoral neck BMD values. Application of NOF guidelines to MrOS data estimated that at least 34% of US white men aged 65 years and older and 49% of those aged 75 years and older would be recommended for drug treatment. Application of the new NOF guidelines would result in recommending a very large proportion of white men in the United States for pharmacologic treatment of osteoporosis, for many of whom the efficacy of treatment is unknown.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 02/2010; 25(7):1506-11. · 6.04 Impact Factor
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S P Moffett,
J I Oakley,
J A Cauley,
L Y Lui,
K E Ensrud,
B C Taylor,
T A Hillier,
M C Hochberg,
J Li,
S Cayabyab,
J M Lee,
G Peltz, S R Cummings,
J M Zmuda
[show abstract]
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ABSTRACT: Osteoprotegerin (OPG) is a soluble decoy receptor for receptor activator nuclear factor kappa-beta that blocks osteoclastic bone resorption.
We investigated the association between a Lys3Asn polymorphism in the OPG gene and bone mineral density (BMD), and the risk of fracture in 6695 women aged 65 yr and older participating in the Study of Osteoporotic Fractures.
BMD was measured using either single-photon absorptiometry (Osteon Osteoanalyzer; Dove Medical Group, Los Angeles, CA) or dual-energy x-ray absorptiometry (Hologic QDR 1000; Hologic, Inc., Bedford, MA). Incident fractures were confirmed by physician adjudication of radiology reports. Genotyping was performed using an immobilized probe-based assay.
Women who were homozygous for the minor G (Lys) allele had significantly lower BMD at the intertrochanter, distal radius, lumbar spine, and calcaneus than those with the C (Asn) allele. There were 701 incident hip fractures during 13.6-yr follow-up (91,249 person-years), including 362 femoral neck and 333 intertrochanteric hip fractures. Women with the C/C (Asn-Asn) genotype had a 51% higher risk of femoral neck fracture (95% confidence interval, 1.13-2.02) and 26% higher risk of hip fracture (95% confidence interval, 1.02-1.54) than those with the G/G (Lys-Lys) genotype. These associations were independent of BMD. Intertrochanteric fractures were not associated with the Lys3Asn polymorphism.
These results require confirmation but suggest a role for the OPG Lys3Asn polymorphism in the genetic susceptibility to hip fractures among older white women.
Journal of Clinical Endocrinology & Metabolism 06/2008; 93(5):2002-8. · 6.50 Impact Factor
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ABSTRACT: The Pro12Ala polymorphism of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has been associated with decreased risk of diabetes and obesity, both disorders linked to cognitive impairment. We tested whether this polymorphism is associated with cognition.
Two thousand nine hundred sixty-one participants (mean age, 74.1; 41% Black; 52% women) were administered the Modified Mini-Mental State Examination (3MS) and Digit Symbol Substitution Test (DSST) at baseline and 4 year follow-up. Test scores were adjusted for age, sex, education, cerebrovascular disease, depression and APOE genotype and additionally for race. We determined the association between Ala allele and development of cognitive decline (3MS decline of > or = 5 points).
At baseline, unadjusted scores on both cognitive tests were higher for Ala carriers compared to non-carriers (3MS, 94.2 versus 92.5, p<0.001; DSST, 40.2 versus 34.5, p<0.001). Similarly, follow-up scores were higher for Ala carriers. Multivariable adjustment led to similar results; additional adjustment for race attenuated the baseline 3MS results. After 4 years, 17.5% of Ala carriers developed cognitive decline compared to 25% among non-carriers (unadjusted OR=0.61; 95%CI, 0.46-0.82; adjusted OR=0.75; 95%CI, 0.55-1.02). Further adjustment for metabolic variables including fasting blood glucose and lipid level did not change the results.
The PPAR-gamma Ala12 allele carriers may have less risk of developing cognitive decline.
Neurobiology of aging 02/2008; 29(1):78-83. · 5.94 Impact Factor
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ABSTRACT: Quantitative ultrasound (QUS) is associated with fracture risk in women, but there are few data in men. We studied 5,607 older men and found that QUS predicts hip and any non-spine fracture risk nearly as well as BMD. Combined measurements of QUS and BMD are not superior to either measurement alone.
Quantitative ultrasound (QUS) predicts fracture risk among older women, but there are few prospective studies among older men. We studied the ability of QUS and BMD measurements to predict hip and other non-spine fractures in a population-based study of older men.
Calcaneal QUS and hip BMD were measured in 5,607 men aged > or =65 years recruited from six US centers. At baseline duplicate QUS measurements with repositioning were obtained, and subsequent hip and other non-spine fractures were documented by review of x-rays or x-ray reports. The relationships between QUS and fractures were examined with proportional hazard models adjusted for age and clinic. We used receiver operating characteristic curves and predicted fracture risk models to determine the utility of QUS alone, BMD alone or the combination of QUS+BMD.
During a mean follow-up of 4.2 years with 99% complete follow-up, 239 men suffered a non-spine fracture, including 49 hip fractures. Each standard deviation reduction in broadband ultrasonic attenuation (BUA) was associated with an increased risk of hip (relative hazard=2.0, CI: 1.5, 2.8) and any non-spine fracture (relative hazard=1.6, CI: 1.4, 1.8). The area under the receiver operating characteristic curve and the predicted probability of fracture were similar for BUA alone, BMD alone and the combination of BUA+BMD, indicating that once BUA or BMD is known, the other measurement does not add useful information. Other QUS parameters gave similar results.
QUS measurements predict the risk of hip and any non-spine fracture in older men, and do so nearly as well as hip BMD measurements. Combined measurements of QUS and BMD are not superior to either measurement alone.
Osteoporosis International 06/2007; 18(6):771-7. · 4.58 Impact Factor
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ABSTRACT: Older women treated with conjugated estrogens may have an increased risk of dementia, but the effect of naturally occurring sex hormones on cognition is not certain.
Bioavailable estradiol and free testosterone level were obtained from 792 (55% men, 51% black) participants. We assessed cognition with the Modified Mini-Mental State Examination (3MS), Selective Reminding Test (SRT) and CLOX 1 at baseline and 2 years later.
Women in the lowest estradiol tertile were more likely than those in the highest tertile to decline (> or = 1.0 S.D. of change) on 3MS (25% versus 9%, adjusted odds ratio [OR] = 3.9; 95% confidence interval [CI] = 1.6-9.6) and on SRT (28% versus 12%, adjusted OR [95% CI] = 3.3 [1.4-7.9]) but not CLOX 1. There was a borderline association between low estradiol tertile and decline on SRT in men (22% versus 14%, adjusted OR [95% CI] = 1.9 [0.9-3.9]). Testosterone level was not associated with decline in cognition in either men or women. Findings did not differ by race.
Older women with low estradiol levels were more likely to experience decline in global cognitive function and verbal memory, and a similar trend was observed for verbal memory in men. This supports the hypothesis that endogenous sex hormones may play an important role in the maintenance of cognitive function in older adults.
Neurobiology of aging 03/2007; 28(2):171-8. · 5.94 Impact Factor
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ABSTRACT: To determine whether older women with abdominal aortic calcification had a greater cardiovascular and all-cause mortality, as such data are limited in older adults.
Prospective cohort study with a mean follow-up of 13 years.
Community-based sample with four US clinical centres.
A total of 2056 women aged > or =65 years with abdominal aortic calcification assessed on baseline radiographs.
Mortality rate (all, cardiovascular, cancer or other cause) adjudicated from death certificates and hospital records.
The prevalence of abdominal aortic calcification increased with age, ranging from 60% at age 65-69 years to 96% at 85 years and older. Participants with aortic calcification were more likely to die during follow-up of any cause (47% vs. 27%) or a cardiovascular-specific cause (18% vs. 11%, both P < 0.001) than those without aortic calcification. In age-adjusted analyses, aortic calcification was associated with a greater rate of all-cause and cause-specific mortality (cardiovascular, cancer, and other, all P < or = 0.01). In analyses adjusted for age and cardiovascular risk factors, aortic calcification was associated with an increased rate of all-cause mortality (HR: 1.37, 95% CI: 1.15-1.64), and noncardiovascular noncancer mortality (HR: 1.57, 95% CI: 1.17-2.11). The associations between aortic calcification and cancer mortality (HR: 1.44, 95% CI: 1.00-2.08) or cardiovascular mortality (HR: 1.18, 95% CI: 0.88-1.57) showed a similar pattern without reaching statistical significance, but was slightly stronger for mortality from coronary heart disease (HR: 1.53, 95% CI: 0.91-2.56).
Abdominal aortic calcification in older women is associated with increased mortality. Future research should examine potential mechanisms for this association.
Journal of Internal Medicine 03/2007; 261(3):238-44. · 5.48 Impact Factor
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ABSTRACT: It is commonly believed that the response to treatment in patients on alendronate is proportional to the increase in bone mineral density (BMD), and that those who lose BMD during treatment might not respond to treatment. In the Fracture Intervention Trial 6,459 women were randomly assigned to treatment with alendronate or placebo; BMD was measured annually, and new spine fractures were assessed by lateral spine films, taken at baseline and end of follow-up. Among subjects who took at least 70% of the study drug (5,220 women), we compared reductions in risk of spine fractures at end of follow-up (3 or 4 years) within various levels of change in total hip and spine BMD after 1 and 2 years of treatment, after adjustment for differences in characteristics between the treatment and control groups. Women "losing" BMD at the lumbar spine (0% to 4%) while on alendronate had a reduction of 60% in vertebral fracture risk [OR = 0.40 (0.16, 0.99)] compared to their counterparts in the placebo group. The few women that lost more than 4% did not have a significant benefit [OR = 0.15 (0.02, 1.29)]. Those who "gained" BMD (0% to 4%) during treatment had a reduction in risk of 51% [OR = 0.49 (0.30, 0.78)]. Similarly, women who "lost" total hip BMD (0% to 4%) during the first year on alendronate had a 53% decreased risk of vertebral fracture compared to their controls taking placebo [OR = 0.47 (0.27, 0.81)], whereas those "gaining" BMD (0% to 4%) had a comparable risk reduction [OR = 0.49 (0.34, 0.71)]. This was not observed for the few women who lost more than 4% [OR = 0.61 (0.11, 3.45)]. Patients who lost BMD at both the hip and spine were not protected by alendronate. Among patients who adhere to treatment with alendronate, even those who lose BMD benefit from a substantial reduction in risk of vertebral fracture. So, the reduction in bone turnover induced by alendronate might be more important than BMD changes. The few women who lose the most BMD (more than 4% per year) might not benefit from the treatment.
Osteoporosis International 08/2005; 16(7):842-8. · 4.58 Impact Factor
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S P Moffett,
J M Zmuda,
J I Oakley,
T J Beck,
J A Cauley,
K L Stone,
Li-Yung Lui,
K E Ensrud,
T A Hillier,
M C Hochberg,
P Morin,
G Peltz,
D Greene, S R Cummings
[show abstract]
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ABSTRACT: TNFalpha is a proinflammatory cytokine that promotes osteoclastic bone resorption. We evaluated the association between a G-308A polymorphism (rs1800629) at the TNFA locus and osteoporosis phenotypes in 4306 older women participating in the Study of Osteoporotic Fractures. Femoral neck bone mineral density (BMD) and structural geometry were measured using dual-energy x-ray absorptiometry and hip structural analysis. Incident fractures were confirmed by physician adjudication of radiology reports. Despite similar femoral neck BMD, women with the A/A genotype had greater subperiosteal width (P = 0.01) and endocortical diameter (P = 0.03) than those with the G/G genotype. The net result of these structural differences was that there was a greater distribution of bone mass away from the neutral axis of the femoral neck in women with the A/A genotype, resulting in greater indices of bone bending strength (cross-sectional moment of inertia: P = 0.004; section modulus: P = 0.003). Among 376 incident hip fractures during 12.1 yr of follow-up, a 22% decrease in the risk of hip fracture was seen per copy of the A allele (relative risk 0.78; 95% confidence interval 0.63, 0.96), which was not influenced by adjustments for potential confounding factors, BMD, or bone strength indices. The G-308A polymorphism was not associated with a reduced risk of other fractures. These results suggest a potential role of genetic variation in TNFalpha in the etiology of osteoporosis.
Journal of Clinical Endocrinology & Metabolism 07/2005; 90(6):3491-7. · 6.50 Impact Factor
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T J Key,
P N Appleby,
G K Reeves,
A Roddam,
J F Dorgan,
C Longcope,
F Z Stanczyk,
H E Stephenson,
R T Falk,
R Miller, [......],
C E Land,
J A Cauley,
L H Kuller, S R Cummings,
K J Helzlsouer,
A J Alberg,
T L Bush,
G W Comstock,
G B Gordon,
S R Miller
[show abstract]
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ABSTRACT: Obesity is associated with increased breast cancer risk among postmenopausal women. We examined whether this association could be explained by the relationship of body mass index (BMI) with serum sex hormone concentrations.
We analyzed individual data from eight prospective studies of postmenopausal women. Data on BMI and prediagnostic estradiol levels were available for 624 case subjects and 1669 control subjects; data on the other sex hormones were available for fewer subjects. The relative risks (RRs) with 95% confidence intervals (CIs) of breast cancer associated with increasing BMI were estimated by conditional logistic regression on case-control sets, matched within each study for age and recruitment date, and adjusted for parity. All statistical tests were two-sided.
Breast cancer risk increased with increasing BMI (P(trend) =.002), and this increase in RR was substantially reduced by adjustment for serum estrogen concentrations. Adjusting for free estradiol reduced the RR for breast cancer associated with a 5 kg/m2 increase in BMI from 1.19 (95% CI = 1.05 to 1.34) to 1.02 (95% CI = 0.89 to 1.17). The increased risk was also substantially reduced after adjusting for other estrogens (total estradiol, non-sex hormone-binding globulin-bound estradiol, estrone, and estrone sulfate), and moderately reduced after adjusting for sex hormone-binding globulin, whereas adjustment for the androgens (androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone) had little effect on the excess risk.
The results are compatible with the hypothesis that the increase in breast cancer risk with increasing BMI among postmenopausal women is largely the result of the associated increase in estrogens, particularly bioavailable estradiol.
CancerSpectrum Knowledge Environment 09/2003; 95(16):1218-26. · 14.07 Impact Factor
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ABSTRACT: Older persons who have prevalent vertebral fractures have an increased risk of mortality. It is not known whether incident vertebral fractures are also associated with an increased risk of mortality. To determine whether older women with incident vertebral fractures have an increased risk of mortality, we conducted a prospective cohort study of 7233 community-dwelling older women aged 65 years or older who were enrolled in the Study of Osteoporotic Fractures. We measured incident vertebral fractures by radiographic morphometry of paired lateral spine X-rays taken an average of 3.7 years apart. We also collected information on baseline prevalent vertebral fractures; calcaneal bone density; anthropometric measures; and demographic, medical history, and lifestyle variables. Overall mortality was assessed and confirmed by receipt of death certificates. Over an average of 3.7 years, 389 (5.4%) women developed at least one incident vertebral fracture. During an additional 8 years of follow-up, 1617 (22%) women died. Women with at least one new fracture had an age-adjusted 32% increased risk of mortality (RH=1.32; 95% CI=1.10-1.58, P=0.003) compared to those without incident vertebral fractures. After adjustment for weight loss, physical frailty markers, and nine other predictors of mortality, there was no longer an independent association between incident vertebral fractures and mortality (RH=1.06; 95% CI=0.88 1.28). Older women with incident vertebral fractures have an increased risk of mortality that may be explained by weight loss and physical frailty.
Osteoporosis International 08/2003; 14(7):589-94. · 4.58 Impact Factor
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ABSTRACT: Women with hip fracture have an increased risk of second hip fracture but other risk factors for a second hip fracture have not been established. We sought to determine the incidence and risk factors for second hip fracture, in a prospective cohort study of community-dwelling postmenopausal women over 65 years: the Study of Osteoporotic Fractures. From a cohort of 9,704 women, 632 women with a documented first hip fracture during the study were followed up until a second hip fracture or the end of follow-up. Clinical risk factors and bone mineral density were assessed at the beginning of the study. Fifty-three second hip fractures were validated by radiographs. Women with hip fracture had a 2.3% per year risk of second hip fracture. Women who walked for exercise at baseline were less likely to sustain a second hip fracture with a relative risk (RR) of 0.5 [0.3-0.9], as were those who had normal depth perception (RR=0.5 [0.3-0.9]). Women who lost weight since age 25 years had an increased risk of second incident hip fracture (RR = 2.7 [1.6-4.6]), as did those who had a low calcaneal bone mineral density (RR=1.5 [1.1-2.0] per standard deviation decrease in bone mineral density). Current use of estrogen replacement therapy at baseline was protective (RR=0.5 [0.3-0.9]) up to 2 years of follow-up. We conclude that community-dwelling women with a first hip fracture have a high risk of second hip fracture, and risk factors for this second fracture are similar to those of first hip fracture.
Osteoporosis International 05/2003; 14(2):130-6. · 4.58 Impact Factor
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ABSTRACT: Relatively little is known about outcomes following clinical osteoporotic fractures at nonhip, nonvertebral skeletal sites. To address this issue, we prospectively assessed post-fracture disability at multiple skeletal sites in a population of 909 older (aged 55-81 years), community-dwelling women with low femoral neck bone mineral density who had experienced a fracture while enrolled in the Fracture Intervention Trial (FIT). FIT is a randomized, double-masked, placebo-controlled trial that was designed to determine the effect of alendronate on fracture incidence, and the current study was conducted as a secondary analysis of FIT data. Following incident clinical fractures, FIT participants were followed prospectively for assessment of site-specific, fracture-related disability. Measures of disability were self-reported days hospitalized or confined to bed because of the fracture ('bed days') and days of reduced usual activities because of the fracture ('limited activity days'). Of fracture types evaluated, those of the hip resulted in the highest percentage of subjects with any bed days or limited activity days after fracture (94% with any bed days and 100% with any limited activity days), though the mean number of bed days and limited activity days appeared highest after lumbar vertebral fractures (25.8 mean bed days and 158.5 mean limited activity days). Substantial disability also was reported after fractures of thoracic vertebrae, humerus, distal forearm, ankle and foot. Within fracture types, post-fracture disability was highly variable, ranging from none to more than 6 months.
Osteoporosis International 02/2003; 14(1):69-76. · 4.58 Impact Factor
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ABSTRACT: Relatively little is known about outcomes following clinical osteoporotic fractures at nonhip, nonvertebral skeletal sites.
To address this issue, we prospectively assessed post-fracture disability at multiple skeletal sites in a population of 909
older (aged 55–81 years), community-dwelling women with low femoral neck bone mineral density who had experienced a fracture
while enrolled in the Fracture Intervention Trial (FIT). FIT is a randomized, double-masked, placebo-controlled trial that
was designed to determine the effect of alendronate on fracture incidence, and the current study was conducted as a secondary
analysis of FIT data. Following incident clinical fractures, FIT participants were followed prospectively for assessment of
site-specific, fracture-related disability. Measures of disability were self-reported days hospitalized or confined to bed
because of the fracture (`bed days') and days of reduced usual activities because of the fracture (`limited activity days').
Of fracture types evaluated, those of the hip resulted in the highest percentage of subjects with any bed days or limited
activity days after fracture (94% with any bed days and 100% with any limited activity days), though the mean number of bed
days and limited activity days appeared highest after lumbar vertebral fractures (25.8 mean bed days and 158.5 mean limited
activity days). Substantial disability also was reported after fractures of thoracic vertebrae, humerus, distal forearm, ankle
and foot. Within fracture types, post-fracture disability was highly variable, ranging from none to more than 6 months.
Osteoporosis International 12/2002; 14(1):69-76. · 4.58 Impact Factor
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ABSTRACT: The use of biochemical markers of bone turnover has been advocated to improve follow-up of women receiving antiresorptive therapies for osteoporosis, but this strategy is not yet supported by trials showing it improves effectiveness of treatments. To explore the potential value of markers of bone turnover to monitor antiresorptive treatments of osteoporosis, we conducted a decision analysis using a decision tree and Markov modeling. We have compared two strategies: treatment of a woman without specific monitoring; and treatment of this woman with measurement of a serum marker of bone resorption after 3 months of treatment, with change of treatment if response to treatment assessed by this marker was not satisfactory. The base case is the treatment of a 60-year-old osteoporotic woman with a total hip T-score of -3, using a second generation bisphosphonate during 5 years. We found that follow-up produced slightly greater quality adjusted life years (QALYs) than no follow-up (8.1560 vs 8.1532, i.e. a one day difference). In a two-way sensitivity analysis, the follow-up option produced higher QALYs so long as adherence rate with follow-up was equal or superior to the proportion of women who adhered without follow-up. For example, if the proportion of women adherent to treatment was increased from 50% to 60% by follow-up, then the expected value of the follow-up branch was increased from 8.1560 QALYs to 8.1800 QALYs (i.e. a difference of 9 days). In addition, the higher the non-response rate, the greater the benefit from monitoring with a biochemical marker. In conclusion, our decision analysis model suggests that follow-up of osteoporotic women treated with a second generation bisphosphonate during a 5-year period using an early measurement of a serum marker of bone resorption may increase effectiveness of the treatment on quality of life, but the effect is very small. So, the use of follow-up measures of bone turnover may be based on patient and physician preferences.
Osteoporosis International 10/2002; 13(9):738-44. · 4.58 Impact Factor
