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J A Eisman

Publications and source records attributed to J A Eisman.

At least 19 recordsLinked to original sources
PubMed2006

A randomized study of two different information-based interventions on the management of osteoporosis in minimal and moderate trauma fractures.

INTRODUCTION: Despite the high risk for subsequent fracture following an initial osteoporotic fracture, the majority of subjects with minimal trauma fractures receive no treatment for osteoporosis. The primary aim of this investigation was to determine whether an information-based intervention could change post-fracture management of osteoporosis. A secondary aim was to define participant- and doctor-related barriers to osteoporosis management. METHODS: Consecutive fracture patients (n=254) from the outpatient fracture clinic at St Vincent's Hospital, Sydney were interviewed over a 15-month period (February 2002-July 2003). Fracture risk factors, prior investigation and treatment for osteoporosis were collected at baseline. Participants were initially contacted after 3 months to ascertain follow-up management. All those not investigated or treated by their primary care physician were then randomized to either a personalized letter or the same letter plus an offer of a free bone mineral density (BMD) test. Participants were contacted after 9 months to record further investigations or treatment for osteoporosis. RESULTS: Less than 20% of the participants had a primary care physician follow-up 3 months after the fracture, leaving 159 who were randomized to a personalized letter (n=79) and a personalized letter plus the offer of a free BMD test (n=80). There was a significant increase in the number of people investigated for osteoporosis in the group receiving the letter plus BMD offer [38% (letter + BMD) vs. 7% (letter only); p=0.001). A high proportion of those tested had low BMD (49% osteopenia and 17% osteoporosis). However, the rates of treatment in both groups were very low (6%). Furthermore, even among the few individuals (23%) who contacted their primary care physician, only 25% were recommended treatment. The belief that the fracture was osteoporotic was an independent predictor of having a BMD test, a primary care physician follow-up and treatment. Other independent predictors were age over 50 years for a primary care physician follow-up, female sex for having a BMD test and having had a BMD test for treatment. CONCLUSION: This study demonstrates that an information-based intervention led to a modest increase in the proportion of people investigated for osteoporosis; however. there was no significant effect on treatment rates. The offer of a free BMD assessment was associated with a significantly higher rate of investigation than a personalized letter alone (odds ratio: 8.5; 95% confidence interval: 3.1-24.5), but this investigation did not affect treatment rate. The low uptake of either a BMD or a visit to a primary care physician together with low rates of treatment recommendation even among people who contacted their primary care physician reflects significant participant and doctor-related barriers to osteoporosis management.

Adult↗
PubMed2006

The use of multiple sites for the diagnosis of osteoporosis.

INTRODUCTION: It has been suggested that bone mineral density (BMD) measurements should be made at multiple sites, and that the lowest T-score should be taken for the purpose of diagnosing osteoporosis. PURPOSE: The aim of this study was to examine the use of BMD measurements at the femoral neck and lumbar spine alone and in combination for fracture prediction. METHODS: We studied 19,071 individuals (68% women) from six prospective population-based cohorts in whom BMD was measured at both sites and fracture outcomes documented over 73,499 patient years. BMD values were converted to Z-scores, and the gradient of risk for any osteoporotic fracture and for hip fracture was examined by using a Poisson model in each cohort and each gender separately. Results of the different studies were merged using weighted beta-coefficients. RESULTS: The gradients of risk for osteoporotic fracture and for hip fracture were similar in men and women. In men and women combined, the risk of any osteoporotic fracture increased by 1.51 [95% confidence interval (CI)=1.42-1.61] per standard deviation (SD) decrease in femoral-neck BMD. For measurements made at the lumbar spine, the gradient of risk was 1.47 (95% CI=1.38-1.56). Where the minimum of the two values was used, the gradient of risk was similar (1.55; 95% CI=1.45-1.64). Higher gradients of risk were observed for hip fracture outcomes: with BMD at the femoral neck, the gradient of risk was 2.45 (95% CI=2.10-2.87), with lumbar BMD was 1.57 (95% CI=1.36-1.82), and with the minimum value of either femoral neck and lumbar spine was 2.11 (95% CI=1.81-2.45). Thus, selecting the lowest value for BMD at either the femoral neck or lumbar spine did not increase the predictive ability of BMD tests. By contrast, the sensitivity increased so that more individuals were identified but at the expense of specificity. Thus, the same effect could be achieved by using a less stringent T-score for the diagnosis of osteoporosis. CONCLUSIONS: Since taking the minimum value of the two measurements does not improve predictive ability, its clinical utility for the diagnosis of osteoporosis is low.

Absorptiometry, Photon↗
PubMed2006

Risk factors for vitamin D inadequacy among women with osteoporosis: an international epidemiological study.

A serum 25-hydroxyvitamin D [25(OH)D] level of 75 nmol/l (30 ng/ml) has been proposed as the minimum for adequate vitamin D nutrition as lower levels are associated with increases in serum parathyroid hormone in otherwise healthy adults. Amongst 2589 community-dwelling, postmenopausal women with osteoporosis from 18 countries, recruited to determine risk factors for vitamin D inadequacy, 64% had vitamin D inadequacy. General health, education, ethnicity, sun exposure, skin reactivity, diet, recent travel to sunny climates, vitamin D supplementation, body mass index (BMI), season and latitude were assessed using logistic regression models. Asian ethnicity, BMI >or=30 kg/m(2), living in non-equatorial countries, inadequate vitamin D supplementation, poor/fair health, no education about vitamin D, skin reactivity and no recent travel to sunny areas were significant predictors. Several modifiable risk factors are associated with vitamin D inadequacy worldwide, suggesting potentially simple ways to increase vitamin D and improve bone health in postmenopausal women.

Adult↗
PubMed2005

Body mass index as a predictor of fracture risk: a meta-analysis.

Low body mass index (BMI) is a well-documented risk factor for future fracture. The aim of this study was to quantify this effect and to explore the association of BMI with fracture risk in relation to age, gender and bone mineral density (BMD) from an international perspective using worldwide data. We studied individual participant data from almost 60,000 men and women from 12 prospective population-based cohorts comprising Rotterdam, EVOS/EPOS, CaMos, Rochester, Sheffield, Dubbo, EPIDOS, OFELY, Kuopio, Hiroshima, and two cohorts from Gothenburg, with a total follow-up of over 250,000 person years. The effects of BMI, BMD, age and gender on the risk of any fracture, any osteoporotic fracture, and hip fracture alone was examined using a Poisson regression model in each cohort separately. The results of the different studies were then merged. Without information on BMD, the age-adjusted risk for any type of fracture increased significantly with lower BMI. Overall, the risk ratio (RR) per unit higher BMI was 0.98 (95% confidence interval [CI], 0.97-0.99) for any fracture, 0.97 (95% CI, 0.96-0.98) for osteoporotic fracture and 0.93 (95% CI, 0.91-0.94) for hip fracture (all p <0.001). The RR per unit change in BMI was very similar in men and women ( p >0.30). After adjusting for BMD, these RR became 1 for any fracture or osteoporotic fracture and 0.98 for hip fracture (significant in women). The gradient of fracture risk without adjustment for BMD was not linearly distributed across values for BMI. Instead, the contribution to fracture risk was much more marked at low values of BMI than at values above the median. This nonlinear relation of risk with BMI was most evident for hip fracture risk. When compared with a BMI of 25 kg/m(2), a BMI of 20 kg/m(2) was associated with a nearly twofold increase in risk ratio (RR=1.95; 95% CI, 1.71-2.22) for hip fracture. In contrast, a BMI of 30 kg/m(2), when compared with a BMI of 25 kg/m(2), was associated with only a 17% reduction in hip fracture risk (RR=0.83; 95% CI, 0.69-0.99). We conclude that low BMI confers a risk of substantial importance for all fractures that is largely independent of age and sex, but dependent on BMD. The significance of BMI as a risk factor varies according to the level of BMI. Its validation on an international basis permits the use of this risk factor in case-finding strategies.

Adult↗
PubMed2004

Effects of physical activity and dietary calcium intake on bone mineral density and osteoporosis risk in a rural Thai population.

The objective of the study was to determine the effects of modifiable risk factors on bone mineral density in postmenopausal Thai women. Dietary calcium intake (g/day), energy expenditure (kcal/day), and sunlight exposure (h/day) were assessed in 129 rural Thai women aged 63 years (range 50 to 84 years). Bone mineral density (BMD) at the femoral neck, lumbar spine, and distal radius were measured by dual-energy X-ray absorptiometry (DXA). The average dietary calcium intake was 236 +/- 188 g/day (mean +/- SD), while the energy expenditure was 2,118 +/- 656 kcal/day with 1.1 +/- 1.7 h of sunlight exposure. In multiple linear regression analysis, dietary calcium intake, energy expenditure, and years since menopause were significant and independent predictors of BMD at various sites. The three factors together accounted for between 35% and 45% of the variance of BMD. The prevalence of osteoporosis (defined as BMD T-scores < or =-2.5) was 33% at the femoral neck, 42% at the lumbar spine, and 35% at the distal radius. The risk of osteoporosis was higher in women with lower dietary calcium intake (< or =138 mg/day; prevalence rate ratio [PRR], 1.4; 95% confidence interval [CI], 1.0 to 1.9), lower energy expenditure (< or =1,682 kcal; PRR, 1.7; 95% CI, 1.2 to 2.3), and greater years since menopause (> or =6 years; PRR, 2.6; 95% CI, 1.2 to 5.8). The population attributable risk fraction of osteoporosis risk due to the three factors was 70%. These results suggest that in the Thai population, low dietary calcium intake and low physical activity together with advancing years since menopause were independent risk factors for low BMD.

Aged↗
PubMed2004

Smoking and fracture risk: a meta-analysis.

Smoking is widely considered a risk factor for future fracture. The aim of this study was to quantify this risk on an international basis and to explore the relationship of this risk with age, sex and bone mineral density (BMD). We studied 59,232 men and women (74% female) from ten prospective cohorts comprising EVOS/EPOS, DOES, CaMos, Rochester, Sheffield, Rotterdam, Kuopio, Hiroshima and two cohorts from Gothenburg. Cohorts were followed for a total of 250,000 person-years. The effect of current or past smoking, on the risk of any fracture, any osteoporotic fracture and hip fracture alone was examined using a Poisson model for each sex from each cohort. Covariates examined were age, sex and BMD. The results of the different studies were merged using the weighted beta-coefficients. Current smoking was associated with a significantly increased risk of any fracture compared to non-smokers (RR=1.25; 95% Confidence Interval (CI)=1.15-1.36). Risk ratio (RR) was adjusted marginally downward when account was taken of BMD, but it remained significantly increased (RR=1.13). For an osteoporotic fracture, the risk was marginally higher (RR=1.29; 95% CI=1.13-1.28). The highest risk was observed for hip fracture (RR=1.84; 95% CI=1.52-2.22), but this was also somewhat lower after adjustment for BMD (RR=1.60; 95% CI=1.27-2.02). Risk ratios were significantly higher in men than in women for all fractures and for osteoporotic fractures, but not for hip fracture. Low BMD accounted for only 23% of the smoking-related risk of hip fracture. Adjustment for body mass index had a small downward effect on risk for all fracture outcomes. For osteoporotic fracture, the risk ratio increased with age, but decreased with age for hip fracture. A smoking history was associated with a significantly increased risk of fracture compared with individuals with no smoking history, but the risk ratios were lower than for current smoking. We conclude that a history of smoking results in fracture risk that is substantially greater than that explained by measurement of BMD. Its validation on an international basis permits the use of this risk factor in case finding strategies.

Age Distribution↗
PubMed2004

A family history of fracture and fracture risk: a meta-analysis.

The aims of the present study were to determine whether a parental history of any fracture or hip fracture specifically are significant risk factors for future fracture in an international setting, and to explore the effects of age, sex and bone mineral density (BMD) on this risk. We studied 34,928 men and women from seven prospectively studied cohorts followed for 134,374 person-years. The cohorts comprised the EPOS/EVOS study, CaMos, the Rotterdam Study, DOES and cohorts at Sheffield, Rochester and Gothenburg. The effect of family history of osteoporotic fracture or of hip fracture in first-degree relatives, BMD and age on all clinical fracture, osteoporotic fracture and hip fracture risk alone was examined using Poisson regression in each cohort and for each sex. The results of the different studies were merged from the weighted beta coefficients. A parental history of fracture was associated with a modest but significantly increased risk of any fracture, osteoporotic fracture and hip fracture in men and women combined. The risk ratio (RR) for any fracture was 1.17 (95% CI=1.07-1.28), for any osteoporotic fracture was 1.18 (95% CI=1.06-1.31), and for hip fracture was 1.49 (95% CI=1.17-1.89). The risk ratio was higher at younger ages but not significantly so. No significant difference in risk was seen between men and women with a parental history for any fracture (RR=1.17 and 1.17, respectively) or for an osteoporotic fracture (RR=1.17 and 1.18, respectively). For hip fracture, the risk ratios were somewhat higher, but not significantly higher, in men than in women (RR=2.02 and 1.38, respectively). A family history of hip fracture in parents was associated with a significant risk both of all osteoporotic fracture (RR 1.54; 95CI=1.25-1.88) and of hip fracture (RR=2.27; 95% CI=1.47-3.49). The risk was not significantly changed when BMD was added to the model. We conclude that a parental history of fracture (particularly a family history of hip fracture) confers an increased risk of fracture that is independent of BMD. Its identification on an international basis supports the use of this risk factor in case-finding strategies.

Age Factors↗
PubMed2004

Upper gastrointestinal and overall tolerability of alendronate once weekly in patients with osteoporosis: results of a randomized, double-blind, placebo-controlled study.

OBJECTIVE: To compare the upper gastrointestinal (GI) and overall tolerability profiles of alendronate 70 mg once weekly with placebo. RESEARCH DESIGN AND METHODS: This 12-week international, multi-center, randomized, double-blind, placebo-controlled trial included 449 postmenopausal women and men with osteoporosis at 44 sites in 19 countries in Europe, the Americas, Africa, and Asia-Pacific. Subjects were randomized to alendronate 70 mg once weekly or matching placebo in a 1:1 ratio. MAIN OUTCOME MEASURES: The safety and tolerability of weekly alendronate and placebo were captured as clinical and laboratory adverse events. The primary endpoint was upper GI tolerability based on the incidence of upper GI tract adverse events. Secondary endpoints included the percentage of subjects who discontinued therapy due to a drug-related upper GI adverse event. Change from baseline in bone turnover as measured by the urinary N-telopeptide-collagen crosslinks corrected for creatinine (NTx/Cr) was assessed at 12 weeks as an indicator of efficacy. RESULTS: The percentages of subjects reporting an upper GI tract adverse event in the alendronate 70 mg once weekly group (9.8%) and the placebo group (9.4%) were similar. The risk difference between the two treatment groups (alendronate minus placebo) was 0.4% [95% confidence interval (CI), -5.1%, 5.9%]. Percentages of subjects who discontinued due to a drug-related upper GI adverse event were also similar (alendronate 2.7%; placebo 2.2%; risk difference 0.4%, 95% CI, -2.4, 3.3). The overall tolerability profile of alendronate 70 mg once weekly, as measured by the percentage 8.0% (95% CI, 1.4%, 15.0%) increase in the of subjects reporting any adverse event, was similar to that of placebo (risk difference 2.1%, 95% CI -6.9, 11.0). There was a significant 43.3% (95% CI, -47.9%, -38.3%) decrease from baseline in urinary NTx/Cr in the alendronate group compared with an placebo group at Week 12. CONCLUSION: Alendronate 70 mg administered once weekly to women and men with osteoporosis has an upper GI and overall tolerability profile similar to that of placebo.

Administration, Oral↗
PubMed2003

Targeted overexpression of vitamin D receptor in osteoblasts increases calcium concentration without affecting structural properties of bone mineral crystals.

Increased cross-sectional area and strength of long bones has been observed in transgenic mice with 2-fold (OSV9) and 3-fold (OSV3) elevation of osteoblast vitamin D receptor (VDR) levels. In the present study, mineralization density distributions, including typical calcium content (Ca(Peak)) and homogeneity of mineralization (Ca(Width)) of femoral bone and growth plate cartilage, were determined by quantitative backscattered electron imaging (qBEI). Fourier-transform infrared (FTIR) microspectroscopy was used to examine mineral content, collagen and crystal maturation, and scanning small angle X-ray scattering (scanning-SAXS) for studying mineral particle thickness and alignment. In addition, X-ray diffraction (XRD) of distal tibiae revealed mineral particle c-axis size. In trabecular bone, the increase in Ca(Peak) was significant for both OSV9 (+ 3.14%, P = 0.03) and OSV3 (+ 3.43%, P = 0.02) versus controls with 23.61 +/- 0.45 S.D. wt% Ca baseline values. In cortical bone, Ca(Peak) was enhanced for the OSV3 mice (+ 1.84%, P = 0.02) versus controls with 26.61 +/- 0.28 S.D. wt% Ca, and OSV9 having intermediate values. Additionally, there was significantly increased homogeneity of mineralization as denoted by a reduction of Ca(Width) (-8.4%, P = 0.01) in primary spongiosa. FTIR microspectroscopy, with the exception of an increased collagen maturity in OSV3 trabecular bone (+ 9.9%, P = 0.02), XRD, and scanning-SAXS indicated no alterations in the nanostructure of transgenic bone. These findings indicate that elevation of osteoblastic vitamin D response led to formation of normal bone with higher calcium content. These material properties, together with indications of decreased bone resorption in secondary spongiosa and increased cortical periosteal bone formation, appear to contribute to the improved mechanical properties of their long bones and suggest an important physiological role of the vitamin D-endocrine system in normal bone mineralization.

Animals↗
PubMed2001

Osteopenia in HIV-infected men: association with asymptomatic lactic acidemia and lower weight pre-antiretroviral therapy.

BACKGROUND: Osteopenia has been associated with antiretroviral therapy, particularly with protease inhibitors. Osteopenia in HIV-uninfected men is associated with mitochondrial defects. METHODS: Bone density was assessed by dual-energy X-ray absorptiometry (DEXA) in 221 HIV-infected men (mean age 43 years) recruited to a lipodystrophy prevalence survey. Additional parameters assessed were demographics, exercise, smoking, type(s) and duration of all antiretroviral therapy, lipodystrophy (overall and by region), CD4 counts, HIV RNA, fasting metabolic parameters (lipid, glycaemic, lactate, liver enzymes, testosterone) and regional body fat and lean mass (DEXA and L4 abdominal computed tomographic scan). RESULTS: Thirty-two patients were drug-naive; 42 were receiving nucleoside analogue reverse transcriptase inhibitors (NRTI) and 147 were receiving these plus protease inhibitors. Osteoporosis (t-score < -2.5 SD below normal) was found in seven (3%) and osteopenia (t-score -1.0 to -2.5 SD) in 44 (22%). No patient had had a fracture since being infected with HIV. The only factors independently associated on logistic regression with osteopenia or osteoporosis were higher lactate levels, even if asymptomatic [odds ratio (OR) 2.39 per 1 mmol/l increase; 95% confidence interval (CI) 1.39-4.11; P = 0.002), and lower weight prior to commencing antiretroviral therapy (OR 1.06 per 1 kg decrease; 95% CI 1.02-1.11; P = 0.006). There was no independent association with any other parameter, including type or duration of antiretroviral therapy and lipodystrophy at any site. Lower total bone mineral density was associated with lower weight prior to commencing antiretroviral therapy whereas lower spinal bone mineral density was associated mostly with higher lactate. CONCLUSION: Osteopenia in HIV-infected men is common, asymptomatic and is associated with asymptomatic NRTI-related lactic acidemia and lower weight pre-antiretroviral therapy.

Absorptiometry, Photon↗
PubMed2001

Risk factors for proximal humerus, forearm, and wrist fractures in elderly men and women: the Dubbo Osteoporosis Epidemiology Study.

Fractures of the proximal humerus, forearm, and wrist account for approximately one third of total osteoporotic fractures in the elderly. Several risk factors for these fractures were evaluated in this prospective study of 739 men and 1,105 women aged > or =60 years in Dubbo, Australia. During follow-up (1989-1996), the respective incidences of humerus and of forearm and wrist fractures, per 10,000 person-years, were 22.6 and 33.8 for men and 54.8 and 124.6 for women. Independent predictors of humerus fracture were femoral neck bone mineral density (FNBMD) (relative risk (RR) = 2.3, 95% confidence interval (CI): 1.2, 4.5) in men and FNBMD (RR = 2.4, 95% CI: 1.7, 3.5) and height loss (RR = 1.1, 95% CI: 1.0, 1.2) in women. For forearm and wrist fractures, risk factors were FNBMD (men: RR = 1.5, 95% CI: 1.0, 2.3; women: RR = 1.5, 95% CI: 1.2, 1.9) and height loss (men: RR = 1.2, 95% CI: 1.0, 1.3; women: RR = 1.1, 95% CI: 1.0, 1.2). In addition, dietary calcium (men: RR = 2.0, 95% CI: 1.0, 3.6) and a history of falls (women: RR = 1.9, 95% CI: 1.4, 2.6) were also significant. These data suggest that elderly men and women largely share common risk factors for upper limb fractures and that FNBMD is the primary risk factor.

Accidental Falls↗
PubMed2001

Ski-interacting protein interacts with Smad proteins to augment transforming growth factor-beta-dependent transcription.

Transforming growth factor-beta (TGF-beta) signaling requires the action of Smad proteins in association with other DNA-binding factors and coactivator and corepressor proteins to modulate target gene transcription. Smad2 and Smad3 both associate with the c-Ski and Sno oncoproteins to repress transcription of Smad target genes via recruitment of a nuclear corepressor complex. Ski-interacting protein (SKIP), a nuclear hormone receptor coactivator, was examined as a possible modulator of transcriptional regulation of the TGF-beta-responsive promoter from the plasminogen activator inhibitor gene-1. SKIP augmented TGF-beta-dependent transactivation in contrast to Ski/Sno-dependent repression of this reporter. SKIP interacted with Smad2 and Smad3 proteins in vivo in yeast and in mammalian cells through a region of SKIP between amino acids 201-333. In vitro, deletion of the Mad homology domain 2 (MH2) domain of Smad3 abrogated SKIP binding, like Ski/Sno, but the MH2 domain of Smad3 alone was not sufficient for protein-protein interaction. Overexpression of SKIP partially overcame Ski/Sno-dependent repression, whereas Ski/Sno overexpression attenuated SKIP augmentation of TGF-beta-dependent transcription. Our results suggest a potential mechanism for transcriptional control of TGF-beta signaling that involves the opposing and competitive actions of SKIP and Smad MH2-interacting factors, such as Ski and/or Sno. Thus, SKIP appears to modulate both TGF-beta and nuclear hormone receptor signaling pathways.

Animals↗
PubMed2001

Cross-talk between 1,25-dihydroxyvitamin D3 and transforming growth factor-beta signaling requires binding of VDR and Smad3 proteins to their cognate DNA recognition elements.

1,25-Dihydroxyvitamin D(3) (vitamin D) and transforming growth factor-beta (TGF-beta) regulate diverse biological processes including cell proliferation and differentiation through modulation of the expression of target genes. Members of the Smad family of proteins function as effectors of TGF-beta signaling pathways whereas the vitamin D receptor (VDR) confers vitamin D signaling. We investigated the molecular mechanisms by which TGF-beta and vitamin D signaling pathways interact in the regulation of the human osteocalcin promoter. Synergistic activation of the osteocalcin gene promoter by TGF-beta and vitamin D was observed in transient transfection experiments. However, in contrast to a previous report by Yanagisawa, J., Yanagi, Y., Masuhiro, Y., Suzawa, M., Watanabe, M., Kashiwagi, K., Toriyabe, T., Kawabata, M., Miyazono, K., and Kato, S. (1999) Science, 283, 1317-1321, synergistic activation was not detectable when the osteocalcin vitamin D response element (VDRE) alone was linked to a heterologous promoter. Inclusion of the Smad binding elements (SBEs) with the VDRE in the heterologous promoter restored synergistic activation. Furthermore, this synergy was dependent on the spacing between VDRE and SBEs. The Smad3-Smad4 heterodimer was found to bind in gel shift assay to two distinct DNA segments of the osteocalcin promoter: -1030 to -989 (SBE3) and -418 to -349 (SBE1). Deletion of SBE1, which is proximal to the VDRE, but not the distal SBE3 in this promoter reporter abolished TGF-beta responsiveness and eliminated synergistic co-activation with vitamin D. Thus the molecular mechanism, whereby Smad3 and VDR mediate cross-talk between the TGF-beta and vitamin D signaling pathways, requires both a VDRE and a SBE located in close proximity to the target promoter.

Animals↗
PubMed2001

Bone mineral density in prepubertal asthmatics receiving corticosteroid treatment.

OBJECTIVE: To examine whether bone mass is reduced in prepubertal, asthmatics receiving high doses of inhaled corticosteroids. METHODOLOGY: A cross-sectional comparison of lumbar spine-bone mineral density (LS-BMD) was undertaken in 76 subjects after stratifying them according to dosage and administration route of corticosteroid. RESULTS: Weight was the only independent predictor of LS-BMD (r(2) = 0.38). Children receiving greater than 800 microg/day of inhaled corticosteroid plus intermittent oral corticosteroid had a significantly lower weight-adjusted LS-BMD than children treated with 400-800 microg/day of inhaled corticosteroid (mean difference: 0.06 g/cm(2), 95% confidence interval (CI): - 0.02 to - 0.10). A significant difference in weight-adjusted LS-BMD persisted when all children receiving greater than 800 microg/day of inhaled corticosteroid, irrespective of additional oral corticosteroid treatment, were compared with children receiving 400-800 microg/day of inhaled corticosteroid (mean difference: - 0.05 g/cm(2), 95%CI interval: -0.02 to - 0.09). Bone mass was similar in children not receiving any inhaled corticosteroid and those treated with 400-800 microg/day of inhaled corticosteroid. CONCLUSIONS: A reduced bone mass in prepubertal asthmatic children receiving high doses of inhaled corticosteroids may predetermine a compromised peak bone mass and increase osteoporotic fracture risk in adulthood.

Absorptiometry, Photon↗
PubMed2001

Glucocorticoid receptor-interacting protein-1 and receptor-associated coactivator-3 differentially interact with the vitamin D receptor (VDR) and regulate VDR-retinoid X receptor transcriptional cross-talk.

The vitamin D(3) receptor (VDR) is a ubiquitously expressed nuclear hormone receptor, and its ligand, calcitriol, has diverse biological effects. The extent to which transcriptional coactivators are involved in modulating tissue-specific functions of the VDR is unclear. Hence, the current studies investigated the role of p160 coactivators in regulating VDR function and interaction with RXR. Two p160 coactivators, glucocorticoid receptor-interacting protein-1 (GRIP1) and receptor-associated coactivator-3 (RAC3), which are expressed in an inverse fashion in cell lines representative of calcitriol target tissues, interacted directly with the VDR, both in vitro and in yeast cells, but only in the presence of calcitriol. Deletional analyses of VDR indicated that GRIP1 and RAC3 required an intact VDR activation function (AF-2) domain for efficient interaction as well as additional but distinct regions of the VDR. Coexpression experiments in yeast cells indicated that both GRIP1 and RAC3 coassemble with the VDR to form an active transcriptional complex. They also form ternary complexes with VDR homodimers and VDR:RXRalpha heterodimers. In mammalian cells, GRIP1 augmented VDR activation of the osteocalcin promoter, whereas RAC3 enhanced VDR activation indirectly through RXR. These data suggest different coactivators regulate VDR function via distinct mechanisms and support the hypothesis that the VDR recruits different coactivators depending on specific gene and cellular contexts.

Animals↗
PubMed2001

Novel N-terminal variant of human VDR.

The importance of N-terminal regions of nuclear hormone receptors in transcriptional regulation is increasingly recognized. As variant VDR gene transcripts indicated possible N-terminally extended receptors, we investigated their natural occurrence, transactivation capacity, and subcellular localization. A novel 54-kDa VDRB1 protein, in addition to the previously recognized 48-kDa VDRA form, was detected in human kidney tissue as well as in osteoblastic (MG63), intestinal (Int-407, DLD-1, and COLO 206F), and kidney epithelial (786) human cell lines by Western blots using isoform-specific and nonselective anti-VDR antibodies. VDRB1 was present at approximately one-third the level of VDRA. Isoform-specific VDRB1 expression constructs produced lower ligand-dependent transactivation than VDRA when transiently transfected with a vitamin D-responsive promoter into cell lines with low endogenous VDR. Intracellular localization patterns of the green fluorescent protein-tagged VDR isoforms differed. VDRB1 appeared as discrete intranuclear foci in the absence of 1,25-dihydroxyvitamin D3, whereas VDRA produced diffuse nuclear fluorescence. After 1,25-dihydroxyvitamin D3 treatment, both VDR isoforms exhibited similar diffuse nuclear signal. In the absence of 1,25-dihydroxyvitamin D3, the VDRB1 foci partially colocalized with SC-35 speckles and a subset of promyelocytic leukemia nuclear bodies. These data provide the first evidence of VDRB1, a novel N-terminally variant human VDR that is expressed at a level comparable to VDRA in human tissue and cell lines. It is characterized by reduced transactivation activity and a ligand-responsive speckled intranuclear localization. The intranuclear compartmentalization and altered functional activity of VDRB1 may mediate a specialized physiological role for this receptor isoform.

Cell Line↗
PubMed2001

Genetic control of bone density and turnover: role of the collagen 1alpha1, estrogen receptor, and vitamin D receptor genes.

Genetic factors are known to influence both the peak bone mass and probably the rate of change in bone density. A range of regulatory and structural genes has been proposed to be involved including collagen 1alpha (COL1A1), the estrogen receptor (ER), and the vitamin D receptor (VDR), but the actual genes involved are uncertain. We therefore studied the role of the COL1A1 and VDR loci in control of bone density by linkage in 45 dizygotic twin pairs and 29 nuclear families comprising 120 individuals. The influences on bone density of polymorphisms of COL1A1, VDR, and ER were studied by association both cross-sectionally and longitudinally in 193 elderly postmenopausal women (average age, 69 years) over a mean follow-up time of 6.3 years. Weak linkage of the COL1A1 locus with bone density was observed in both twins and families (p = 0.02 in both data sets), confirming previous observations of linkage of this locus with bone density. Association between the MscI polymorphism of COL1A1 and rate of lumbar spine bone loss was observed with significant gene-environment interaction related to dietary calcium intake (p = 0.0006). In the lowest tertile of dietary calcium intake, carriers of "s" alleles lost more bone than "SS" homozygotes (p = 0.01), whereas the opposite was observed in the highest dietary calcium intake (p = 0.003). Association also was observed between rate of bone loss at both the femoral neck and the lumbar spine and the TaqI VDR polymorphism (p = 0.03). This association was strongest in those in the lowest tertile of calcium intake, also suggesting the presence of gene-environment interaction involving dietary calcium and VDR, influencing bone turnover. No significant association was observed between the PvuII ER polymorphism alone or in combination with VDR or COL1A1 genotypes, with either bone density or its rate of change. These data support the involvement of COL1A1 in determination of bone density and the interaction of both COL1A1 and VDR with calcium intake in regulation of change of bone density over time.

Absorptiometry, Photon↗