Search PubMed⌕ Search

Biomedical subjects

E S Orwoll

Publications and source records attributed to E S Orwoll.

At least 19 recordsLinked to original sources
PubMed2006

SHBG gene promoter polymorphisms in men are associated with serum sex hormone-binding globulin, androgen and androgen metabolite levels, and hip bone mineral density.

CONTEXT: SHBG regulates free sex steroid levels, which in turn regulate skeletal homeostasis. Twin studies have demonstrated that genetic factors largely account for interindividual variation in SHBG levels. Glucuronidated androgen metabolites have been proposed as markers of androgenic activity. OBJECTIVE: Our objective was to investigate whether polymorphisms in the SHBG gene promoter [(TAAAA)(n) microsatellite and rs1799941 single-nucleotide polymorphism] are associated with serum levels of SHBG, sex steroids, or bone mineral density (BMD) in men. DESIGN AND STUDY SUBJECTS: We conducted a population-based study of two cohorts of Swedish men: elderly men (MrOS Sweden; n congruent with 3000; average age, 75.4 yr) and young adult men (GOOD study; n = 1068; average age, 18.9 yr). MAIN OUTCOME MEASURES: We measured serum levels of SHBG, testosterone, estradiol, dihydrotestosterone, 5alpha-androstane-3alpha,17beta-diol glucuronides, androsterone glucuronide, and BMD determined by dual-energy x-ray absorptiometry. RESULTS: In both cohorts, (TAAAA)(n) and rs1799941 genotypes were associated with serum levels of SHBG (P < 0.001), dihydrotestosterone (P < 0.05), and 5alpha-androstane-3alpha,17beta-diol glucuronides (P < 0.05). In the elderly men, they were also associated with testosterone and BMD at all hip bone sites. The genotype associated with high levels of SHBG was also associated with high BMD. Interestingly, male mice overexpressing human SHBG had increased cortical bone mineral content in the femur, suggesting that elevated SHBG levels may cause increased bone mass. CONCLUSIONS: Our findings demonstrate that polymorphisms in the SHBG promoter predict serum levels of SHBG, androgens, and glucuronidated androgen metabolites, and hip BMD in men.

Adolescent↗
PubMed2003

Men, bone and estrogen: unresolved issues.

Gonadal function has long been known to be important for skeletal health in men. Prepubertal hypogonadism is clearly associated with impairment in peak bone mass development and adult-onset hypogonadism with accelerated bone loss. Gonadal failure results in deficits in both androgen and estrogen action, but traditionally androgens were assumed to have the most important skeletal effect in men. Recently that model has been reconsidered as a variety of kinds of evidence have appeared to document a critical role for estrogen in bone physiology. As a result of this fresh perspective a host of interesting new dilemmas and hypotheses are being examined, including those related to the mechanisms of sex steroid action in bone, the origins of gender differences in skeletal morphology and physiology, and the role of estrogen in diagnostic and therapeutic strategies in men with metabolic bone disorders.

Adult↗
PubMed2003

An investigation of the predictors of bone mineral density and response to therapy with alendronate in osteoporotic men.

Male osteoporosis is an important disease, with 25-30% of all hip fractures occurring in men. In a recent randomized, placebo-controlled study of osteoporotic males, alendronate 10 mg daily for 2 yr led to significant increments in bone mineral density (BMD), of a similar magnitude to those observed in postmenopausal women. In this study, specimens collected at intervals during the recent trial of alendronate in male osteoporosis, from 197 of the original 241 participants, were assayed for testosterone, estradiol, IGF-I, IGF binding protein 3 (IGFBP-3), bone-specific alkaline phosphatase [BSAP (serum)], and N-telopeptide of type I collagen corrected for creatinine [NTx (urine)]. Together with fracture and densitometry data from the original study, relationships were examined between BMD and serum IGF-I, IGFBP-3, testosterone, estradiol, BSAP, and urine NTx, both at baseline and during treatment with alendronate, to gain possible insights into the pathogenesis of male osteoporosis. Statistically significant (P <or= 0.05) associations were documented, at baseline, between the presence of vertebral fracture and each of serum IGF-I, serum IGFBP-3, serum free testosterone, total spine BMD, and total body BMD. No statistically significant correlations were observed between any of the baseline variables (IGF-I, IGFBP-3, estradiol, testosterone, and presence of vertebral fracture) and the BMD response to alendronate at any site. In a multivariate analysis, used to identify possible combinations of factors capable of predicting baseline BMD or response to alendronate, statistically significant (P <or= 0.01) relationships were seen, at baseline, between BMD and body mass index, age, and prior fracture. However, no statistically significant relationships were seen between any of the baseline variables (age, body mass index, testosterone, estradiol, IGF-I, IGFBP-3, and prior fracture) and change in BMD at any site. These data suggest that among men with osteoporosis it is not possible to identify patients who would be particularly good candidates for therapy with alendronate on the basis of biochemical or hormonal markers. Alendronate therapy appears to benefit osteoporotic males equally, irrespective of baseline serum testosterone, estradiol, IGF-I, or markers of bone turnover.

Adult↗
PubMed2003

The effect of teriparatide [human parathyroid hormone (1-34)] therapy on bone density in men with osteoporosis.

Teriparatide [rhPTH(1-34)] increases bone mineral density and reduces the risk of vertebral fracture in women. We randomized 437 men with spine or hip bone mineral density more than 2 SD below the young adult male mean to daily injections of placebo, teriparatide 20 microg, or teriparatide 40 microg. All subjects also received supplemental calcium and vitamin D. The study was stopped after a median duration of 11 months because of a finding of osteosarcomas in rats in routine toxicology studies. Biochemical markers of bone formation increased early in the course of therapy and were followed by increases in indices of osteoclastic activity. Spine bone mineral density was greater than in placebo subjects after 3 months of teriparatide therapy, and by the end of therapy it was increased by 5.9% (20 microg) and 9.0% (40 microg) above baseline (p < 0.001 vs. placebo for both comparisons). Femoral neck bone mineral density increased 1.5% (20 microg; p = 0.029) and 2.9% (40 microg; p < 0.001), and whole body bone mineral content increased 0.6% (20 microg; p = 0.021) and 0.9% (40 microg;p = 0.005) above baseline in the teriparatide subjects. There was no change in radial bone mineral density in the teriparatide groups. Bone mineral density responses to teriparatide were similar regardless of gonadal status, age, baseline bone mineral density, body mass index, smoking, or alcohol intake. Subjects experienced expected changes in mineral metabolism. Adverse events were similar in the placebo and 20-microg groups, but more frequent in the 40-microg group. This study shows that teriparatide treatment results in an increase in bone mineral density and is a potentially useful therapy for osteoporosis in men.

Adult↗
PubMed2001

Clinical performance of a highly portable, scanning calcaneal ultrasonometer.

The aim of this study was to establish a normative database, assess precision, and evaluate the ability to identify women with low bone mass and to discriminate women with fracture from those without for a highly portable, scanning calcaneal ultrasonometer: the QUS-2. Fourteen hundred and one Caucasian women were recruited for the study. Among them were 794 healthy women 25-84 years of age evenly distributed per 10-year period to establish a normative database. Of these, 171 aged 25-34 years were defined as the young normal group for the purpose of T-score determination. Precision was assessed within 1 day (short-term) and over a 16-week period (long-term) in 79 women aged 25-84 years. Five hundred twenty-eight women ranging from 50 to 84 years of age with or without prevalent fractures of the spine, hip or forearm were measured to compare the QUS-2 with bone mineral density (BMD) of the hip and spine. Mean calcaneal broadband ultrasound attenuation (BUA) was constant in healthy women from 25 to 54 years of age and decreased with increasing age thereafter. Short-term precision, with and without repositioning of the heel, and long-term precision yielded comparable results (BUA SDs of 2.1-2.4 dB/MHz, coefficients of variations (CVs) of 2.5-2.9%). Calcaneal BUA was significantly correlated with BMD of the total hip (TH), femoral neck (FN) and lumbar spine (LS) in 698 women (r = 0.6-0.7, all p < 0.0001). A similar relationship was observed for LS BMD compared with either TH or FN BMD (r = 0.7, p < 0.0001). Prevalence of osteoporosis in our population (WHO criteria) was 20%, 17%, 21%, and 24% for BUA, BMD of the TH, FN and LS, respectively. Age-adjusted values for a 1 SD reduction in calcaneal BUA and TH and FN BMD predicted prevalent fractures of the spine, forearm, and hip with significant (p < 0.05) odds ratios of 2.3, 2.0 and 2.1, respectively. Areas under the receiver operating characteristic curves for age-adjusted bone mass values predicting prevalent fracture were 0.62 for BUA, 0.59 for TH BMD, 0.60 for FN BMD, and 0.57 for LS BMD; all statistically equivalent. We conclude that the QUS-2 calcaneal ultrasonometer exhibits reproducible clinical performance that is similar to BMD of the spine and hip in identifying women with low bone mass and discriminating women with fracture from those without.

Adult↗
PubMed2001

Androgens: basic biology and clinical implication.

Although androgens have been considered essential modulators of bone biology in men, recent studies have indicated that estrogen may have an important, if not dominant, role. Nevertheless, there is strong evidence that androgens have independent skeletal actions. Nonaromatizable androgens influence a variety of aspects of bone cell biology and are capable of modulating bone remodeling and bone mass. It appears that androgens are particularly important in the control of periosteal bone formation, an effect that might underlie the gender difference in bone size. Alterations in androgen receptor function affect bone metabolism, and new information suggests that androgens modulate receptor homeostasis. The clinical implications of androgen effects, and how they interact with those of estrogens, are somewhat unclear. It is likely that overall bone homeostasis and gender differences depend on a combination of androgenic and estrogenic actions. Androgens may well provide advantages in the prevention and therapy of metabolic bone disorders in both men and women.

Androgens↗
PubMed2001

Phenotypic characterization of mice bred for high and low peak bone mass.

In humans, peak bone mineral density (BMD) is a highly heritable trait and a strong determinant of subsequent osteoporotic fracture risk. To identify the genetic factors responsible for variation in peak BMD, investigators have turned to animal models. In this study we examined the heritability of BMD acquisition and characterized differences in skeletal geometry, histomorphometry, and biomechanical competence between two lines of mice artificially selected for extremes of peak whole body BMD. F2 progeny from a cross between C57BL/6 and DBA/2 inbred strains was used as the foundation population to develop lines selected for either high or low BMD. Whole body BMD was measured by dual-energy X-ray absorptiometry (DXA). By the third generation of selection, highest-scoring BMD (HiBMD) mice exhibited 14% greater peak BMD than lowest-scoring BMD (LoBMD) mice. The mean realized heritability of peak BMD was 36%. Femoral shaft cortical area and thickness and vertebral cancellous bone volume (BV) were significantly greater (16-30%) in the HiBMD line compared with the LoBMD line. Mean cancellous bone formation rates (BFRs) were 35% lower in HiBMD mice compared with LoBMD mice. Failure load and stiffness in the femoral shaft, femoral neck, and L6 vertebrae were all substantially greater (by 25-190%) in HiBMD mice. Thus, these divergently selected murine lines serve to illustrate some of the means by which genetic mechanisms can affect skeletal structure and remodeling. Identification of the individual genes influencing peak BMD in this experimental system will likely reveal some of the genetic determinants of overall bone strength.

Analysis of Variance↗
PubMed2001

Confirmation and fine mapping of chromosomal regions influencing peak bone mass in mice.

Bone mineral density (BMD) is determined by both environmental influences and polygenic inheritance. The extreme difficulty of dissecting out environmental factors from genetic ones in humans has motivated the investigation of animal models. Previously, we used quantitative trait locus (QTL) analysis to examine peak BMD in 24 recombinant inbred (RI) mouse strains, derived from a cross between C57BL/6 (B6) and DBA/2 (D2) progenitors (RI-BXD). The distribution of BMD values among these strains indicated strong genetic influences and a number of chromosomal sites linked to BMD were identified provisionally. Using three additional independent mapping populations derived from the same progenitors, we have confirmed loci on chromosomes 1, 2, and 4, and 11 that contain genes that influence peak BMD. Using a novel fine-mapping approach (RI segregation testing [RIST]), we have substantially narrowed two of the BMD-related chromosomal regions and in the process eliminated a number of candidate genes. The homologous regions in the human genome for each of these murine QTLs have been identified in recent human genetic studies. In light of this, we believe that findings in mice should aid in the identification of specific candidate genes for study in humans.

Animals↗
PubMed2001

Gender specificity in the genetic determinants of peak bone mass.

Peak bone mass is a major determinant of osteoporotic fracture risk. Gender differences in peak bone mass acquisition are well recognized in humans and may account for a substantial share of the increased prevalence of fragility fractures in women compared with men. Skeletal development is regulated by both heritable and environmental factors. Experimental animal models provide a means to circumvent complicating environmental factors. In this study we examined the heritability of peak bone mineral density (BMD) in genetically distinct laboratory mouse strains raised under strict environmental control and sought to identify genetic loci that may contribute to gender differences in this skeletal phenotype. Peak whole body BMD of male and female mice from a panel of 18 recombinant inbred (RI) strains derived from a cross between C57BL/6 and DBA/2 progenitors (BXD) was measured by dual-energy X-ray absorptiometry (DXA). A highly significant relationship existed between body weight and BMD in the BXD RI mice (r2 = 0.25; p = 1 x 10(-43)). To allow for comparison between male and female RI strains, whole body BMD values were corrected for the influence of body weight. The distribution of weight-corrected BMD (WC-BMD) values among the strains indicated the presence of strong genetic influences in both genders, with an estimated narrow sense heritability of 45% and 22% in male and female mice, respectively. Comparison of RI strain results by two-way analysis of variance (ANOVA) revealed a significant strain-by-gender interaction (F1,17,479 = 6.13; p < 0.0001). Quantitative trait locus (QTL) analysis of the BXD RI strain series provisionally identified nine chromosomal sites linked to peak bone mass development in males and seven regions in females. In two cases, the provisional chromosomal loci were shared between genders, but in most cases they were distinct (five female-specific QTLs and six male-specific QTLs). QTL analysis of a genetically heterogeneous F2 population derived from the B6 and D2 progenitor strains provided additional support for the gender specificity of two loci. A significant phenotype-genotype correlation was only observed in male F2 mice at microsatellite marker D7Mit114 on chromosome 7, and a correlation at D2Mit94 on chromosome 2 was only observed in female F2 mice. The present data highlight the important role of gender in the genetic basis of peak bone mass in laboratory mice. Because the male phenotype is associated with considerable fracture risk reduction, an elucidation of the nature of that effect could provide the basis for novel diagnostic, preventative, or therapeutic approaches.

Animals↗
PubMed2001

Does body size account for gender differences in femur bone density and geometry?

The extent to which greater bone strength in men is caused by proportionately greater bone mass versus bigger bone size is not clear, primarily because the larger overall body size of men has made direct comparisons of skeletal measures difficult. We examined gender differences in femur neck (FN) areal bone mineral density (BMD) values collected from 5,623 non-Hispanic whites aged 20+ years in the third National Health and Nutrition Examination Survey (NHANES III, 1988-1994) before and after correction for measured height and weight. We supplemented the conventional areal BMD data (Hologic QDR 1000) with measurements of areal BMD and geometric properties (subperiosteal width, section modulus, and cortical thickness) made at narrow "cross-sectional" regions traversing the FN and the proximal shaft using a structural analysis program. Before body size adjustment, men had significantly higher values than women for all variables at the three measurement sites (p < 0.0001). Adjustment for body size reduced the differences between the sexes for all variables but had a greater effect on BMD (1-8% higher in men) than on geometry (5-17% higher in men). When examined by age, the sex discrepancy was significantly greater in the older group for all variables except subperiosteal widths. We conclude that although body size difference may account for most of the areal BMD difference between men and women, male bones are still bigger in ways that suggest greater bone strength. These differences may contribute importantly to lower fracture risk in men.

Absorptiometry, Photon↗
PubMed2001

Jogging and bone mineral density in men: results from NHANES III.

OBJECTIVES: This cross-sectional population-based study assessed the association of jogging with femoral bone mineral density (BMD) in men. METHODS: Data are from a nationally representative sample of 4254 men aged 20 to 59 years from the Third National Health and Nutrition Examination Survey (NHANES III). Total femoral BMD was measured by dual energy x-ray absorptiometry. Jogging was self-reported. RESULTS: Jogging (any vs none) was strongly associated with higher BMD in multivariate models (P < .01) for both young and middle-aged men. Men who jogged 9 or more times per month had higher BMD levels than those who jogged only 1 to 8 times per month (P = .01). CONCLUSIONS: Jogging is associated with higher femoral neck BMD in men. Additional large-scale studies that measure all aspects of jogging are warranted.

Absorptiometry, Photon↗
PubMed2000

Community water fluoridation, bone mineral density, and fractures: prospective study of effects in older women.

OBJECTIVE: To determine whether fluoridation influences bone mineral density and fractures in older women. DESIGN: Multicentre prospective study on risk factors for osteoporosis and fractures. SETTING: Four community based centres in the United States. PARTICIPANTS: 9704 ambulatory women without bilateral hip replacements enrolled during 1986-8; 7129 provided information on exposure to fluoride. MAIN OUTCOME MEASURES: Bone mineral density of the lumbar spine, proximal femur, radius, and calcaneus plus incident fractures (fractures that occurred during the study) of vertebrae, hip, wrist, and humerus. RESULTS: Women were classified as exposed or not exposed or having unknown exposure to fluoride for each year from 1950 to 1994. Outcomes were compared in women with continuous exposure to fluoridated water for the past 20 years (n=3218) and women with no exposure during the past 20 years (n=2563). In women with continuous exposure mean bone mineral density was 2.6% higher at the femoral neck (0.017 g/cm(2), P<0.001), 2.5% higher at the lumbar spine (0.022 g/cm(2), P<0.001), and 1.9% lower at the distal radius (0.007 g/cm(2), P=0.002). In women with continuous exposure the multivariable adjusted risk of hip fracture was slightly reduced (risk ratio 0.69, 95% confidence interval 0.50 to 0.96, P=0.028) as was the risk of vertebral fracture (0.73, 0.55 to 0.97, P=0.033). There was a non-significant trend toward an increased risk of wrist fracture (1.32, 1.00 to 1.71, P=0.051) and no difference in risk of humerus fracture (0.85, 0.58 to 1.23, P=0.378). CONCLUSIONS: Long term exposure to fluoridated drinking water does not increase the risk of fracture.

Aged↗
PubMed2000

Bisphosphonates: safety and efficacy in the treatment and prevention of osteoporosis.

Osteoporosis affects more than 28 million Americans. With the advent of accessible and affordable diagnostic studies, awareness and recognition of this disease by patients and clinicians are growing. Osteoporotic fractures of the spine and hip are costly and associated with significant morbidity and mortality. Over the past decade, a surge of new antiosteoporotic drugs have been labeled or are awaiting labeling by the U.S. Food and Drug Administration. One class of agents used to treat osteoporosis is the bisphosphonates, which inhibit bone resorption, cause an increase in bone mineral density and reduce the risk of future fractures caused by aging, estrogen deficiency and corticosteroid use. Overall, bisphosphonates have been shown to have a strong safety and tolerability profile.

Alendronate↗
PubMed2000

Determinants of bone mineral density in older men.

Although osteoporosis in men is increasingly recognized as an important health issue and bone mass appears to be a major determinant of fracture, there remain few data concerning the determinants of bone mass in men. To determine the correlates of bone density in men, we studied a large group of older subjects recruited from three rural communities in the northwestern United States. Three hundred and fifty-five men over the age of 60 years (mean 71.5 +/- 7.4 years) without known disorders of mineral metabolism were recruited by community advertising. Bone mineral density was measured at the lumbar spine, proximal femur and radius by dual-energy X-ray absorptiometry, and factors potentially related to skeletal status were assessed by direct measurements or questionnaire. In univariate analyses weight (positively) and age (negatively) were associated with bone density. After adjustment for these two factors, alcohol intake, osteoarthritis and thiazide use were associated with higher bone density, while previous fractures, gastrectomy, peptic ulcer disease, rheumatoid arthritis, glucocorticoid use, hypertension, previous hyperthyroidism, height loss since age 20 years, chronic lung disease and smoking were related to lower density. In multivariate models, only weight and a history of cancer were related to higher bone mass, and age, previous fracture, rheumatoid arthritis, gastrectomy and hypertension were associated with lower density. These data contribute to the emerging field of osteoporosis in men, and may help in the clinical identification of men at higher risk of osteopenia.

Age Distribution↗
PubMed1999

The role of collagen abnormalities in ultrasound and densitometry assessment: In vivo evidence.

There is little information concerning how the mutation of collagen affects bone mineralization and the assessment of bone properties. To estimate these influences, we performed ultrasonic assessments of the calcaneus and bone mineral density (BMD) measurements of the hip and lumbar spine. Females with diseases related to the mutation of collagen [Ehlers-Danlos syndrome (EDS) type III and systemic sclerosis (SSc)] participated in this study. We compared the broadband ultrasound attenuation (BUA and UBI-4), the average transit time through the heel (TTH), and a multiple factor index (UBI-4T) with control subjects matched on age, race, and menstrual status. Both groups of patients had BMD of the spine (L2-L4) within the normal range for their age and sex (for EDS: n = 23, 1.14 +/- 0. 14 g/cm2 and z-score = 0.37; for SSc: n = 15, 0.98 +/- 0.15 g/cm2 and z-score = 0.20). EDS and SSc subjects had lower BMD of the femoral neck (FN) compared with controls (for EDS: 0.91 +/- 0.13 g/cm2, z-score = -0.41, P = 0.025; for SSc 0.67 +/- 0.13 g/cm2, z-score = -0.92, P = 0.006). Subjects with EDS and SSc also had lower BUA values (P = 0.051-0.001) compared with controls. After adjusting for body weight, height, and the level of physical activity, the difference in FN BMD between EDS or SSc and controls became marginal (EDS: P = 0.072; SSc: P = 0.086). However, the significant difference for BUA between subjects and controls remained for EDS (P = 0.008), and disappeared for SSc (0.70) after adjusting for weight, height, level of physical activity, and BMD. These results suggest that the abnormalities of collagen may impact on bone mass measurements differently depending on skeletal site, modality of the assessment, and the source and nature of collagen defects. To determine whether collagen properties influence QUS, proper models in vivo and in vitro should be used.

Absorptiometry, Photon↗