Low Circulating Valine Associate With High Risk of Hip Fractures.

CONTEXT: Hip fractures constitute a major health concern. An adequate supply of amino acids is crucial to ensure optimal acquisition and remodeling of bone. Circulating amino acid levels have been proposed as markers of bone mineral density, but data on their ability to predict incident fractures are scarce. OBJECTIVES: To investigate the associations between circulating amino acids and incident fractures. METHODS: We used UK Biobank (n = 111 257; 901 hip fracture cases) as a discovery cohort and the Umeå Fracture and Osteoporosis (UFO) hip fracture study (hip fracture cases n = 2225; controls n = 2225) for replication. Associations with bone microstructure parameters were tested in a subsample of Osteoporotic Fractures in Men Sweden (n = 449). RESULTS: Circulating valine was robustly associated with hip fractures in the UK Biobank (HR per SD increase 0.79, 95% CI 0.73-0.84), and this finding was replicated in the UFO study (combined meta-analysis including 3126 incident hip fracture cases, odds ratio per SD increase 0.84, 95% CI 0.80-0.88). Detailed bone microstructure analyses showed that high circulating valine was associated with high cortical bone area and trabecular thickness. CONCLUSION: Low circulating valine is a robust predictor of incident hip fractures. We propose that circulating valine may add information for hip fracture prediction. Future studies are warranted to determine whether low valine is causally associated with hip fractures.

Drug information sources in professional work-a questionnaire study on physicians' usage and preferences (the drug information study).

PURPOSE: This study aimed to explore physicians' use of drug information in professional work, with special focus on those working in primary care, and also in relation to personal characteristics of physicians. METHODS: A web-based questionnaire was distributed by e-mail to physicians in five regions in Sweden. The questions concerned drug-related queries at issue when searching for information, sources used, and factors of importance for the choice of source, as well as responder characteristics. RESULTS: A total of 3254 (85%) out of 3814 responding physicians stated that they searched for drug information every week. For physicians working in primary health care, the corresponding number was 585 (96%). The most common drug-related issues searched for by 76% of physicians every week concerned pharmacotherapeutic aspects (e.g., dosing), followed by adverse drug reactions (63%). For 3349 (88%) physicians, credibility was the most important factor for the choice of sources of drug information, followed by easy access online (n = 3127, 82%). Further analyses among physicians in primary care showed that some personal characteristics, like seniority, sex, and country of education, as well as research experience, were associated with usage and preferences of drug information sources. CONCLUSIONS: This study confirms that physicians often use drug information sources in professional work, in particular those who work in primary health care. Credibility and easy access are key factors for usage. Among physicians in primary care, personal factors influenced the choice of drug information sources.

Interaction alerts: A comparison of classifications and recommendations for clinical management between Janusmed and three other knowledge resources.

Classifications of drug interaction alerts differ between knowledge resources, but agreement regarding recommendations for clinical management is less explored. Starting from the medication lists of 274 older patients with ≥2 drugs, all unique drug pairs that triggered a clinically significant interaction alert in Janusmed were included: 100 Category C (manageable by, e.g. dose adjustment) and nine Category D interactions (should be avoided). Out of 109 C/D alerts in Janusmed, 89 (82%), 75 (69%) and 45 (41%) drug pairs triggered an alert of similar clinical significance in Lexicomp, Micromedex® and Stockley's Drug Interactions/Checker (Stockley), respectively. Eight (7%), 20 (18%) and 10 (9%) drug pairs did not trigger any alert in these resources. For 81 (74%), 81 (74%) and 94 (86%) drug pairs, Lexicomp, Micromedex and Stockley provided at least one recommendation for clinical management similar to those provided by Janusmed. For 16 (15%), 9 (8%) and 21 (19%) drug pairs, these resources provided recommendation(s) entirely in agreement with Janusmed. Although many drug pairs elicit alerts of similar significance, and partly concordant recommendations, a non-negligible proportion do not. The findings encourage medical/pharmaceutical reflection by prescribing clinicians and dispensing pharmacists; recommendations provided by knowledge resources vary considerably and cannot be considered definite.

Serum Glycine Levels Are Associated With Cortical Bone Properties and Fracture Risk in Men.

CONTEXT: In a recent study a pattern of 27 metabolites, including serum glycine, associated with bone mineral density (BMD). OBJECTIVE: To investigate associations for serum and urinary glycine levels with BMD, bone microstructure, and fracture risk in men. METHODS: In the population-based Osteoporotic Fractures in Men (MrOS) Sweden study (men, 69-81 years) serum glycine and BMD were measured at baseline (n = 965) and 5-year follow-up (n = 546). Cortical and trabecular bone parameters of the distal tibia were measured at follow-up using high-resolution peripheral quantitative computed tomography. Urinary (n = 2682) glycine was analyzed at baseline. X-ray-validated fractures (n = 594) were ascertained during a median follow-up of 9.6 years. Associations were evaluated using linear regression (bone parameters) or Cox regression (fractures). RESULTS: Circulating glycine levels were inversely associated with femoral neck (FN)-BMD. A meta-analysis (n = 7543) combining MrOS Sweden data with data from 3 other cohorts confirmed a robust inverse association between serum glycine levels and FN-BMD (P = 7.7 × 10-9). Serum glycine was inversely associated with the bone strength parameter failure load in the distal tibia (P = 0.002), mainly as a consequence of an inverse association with cortical cross-sectional area and a direct association with cortical porosity. Both serum and urinary glycine levels predicted major osteoporotic fractures (serum: hazard ratio [HR] per SD increase = 1.22, 95% CI, 1.05-1.43; urine: HR = 1.13, 95% CI, 1.02-1.24). These fracture associations were only marginally reduced in models adjusted by FRAX with BMD. CONCLUSIONS: Serum and urinary glycine are indirectly associated with FN-BMD and cortical bone strength, and directly associated with fracture risk in men.

Student Characteristics Associated with Passing the Exam in Undergraduate Pharmacology Courses-a Cross-sectional Study in Six University Degree Programs.

Adequate knowledge in pharmacology is crucial in many professions but a non-negligible proportion of students fail the exams and knowledge of underlying factors is largely lacking. This study was performed to evaluate to what extent various factors are related to student performance in pharmacology-related courses in higher education, linking administrative data to attendance at non-mandatory teaching sessions and questionnaire replies. A total of 596 students (median age: 22 years; 70% female) were included from eight courses which are part of either the medical, pharmacy, dentistry, nursing, or biomedical analyst degree programs at the Sahlgrenska Academy, Gothenburg, Sweden. In all, 380 (64%) students passed the regular program- and course-specific exam. Multivariate logistic regression analysis revealed that a high participation rate in non-mandatory teaching sessions, as well as a perceived great interest in pharmacology, was associated with students' passing of the exam; adjusted odds ratio (95% confidence interval): 1.30 (1.19 to 1.42; per 10 percentage unit increase in attendance) and 3.38 (1.86 to 6.12), respectively. Working for wages during the course weeks and pre-university grades used in the program application were significant factors in subgroups of students, negatively and positively associated with the exam results, respectively. Age, having Swedish as a second language, and time spent studying were only associated with the exam result in the univariate analyses. To conclude, both students and teachers can contribute significantly to successful education within pharmacology, students by participating in the teaching sessions and teachers by encouraging students to find the subject interesting.

Evidence of a Causal Effect of Estradiol on Fracture Risk in Men.

Context: Observational studies indicate that serum estradiol (E2) is more strongly associated with bone mineral density (BMD) than serum testosterone (T) is, whereas both E2 and T associate with fracture risk in men. Objective: To evaluate the possible causal effect of serum E2 and T on fracture risk in men. Design, Setting, and Participants: A Mendelian randomization (MR) approach was undertaken using individual-level data on genotypes, BMD as estimated by quantitative ultrasound of the heel (eBMD), fractures (n = 17,650), and relevant covariates of 175,583 unrelated men of European origin from the UK Biobank. The genetic instruments for serum E2 and T were taken from the most recent large-scale genome-wide association study meta-analyses on these hormones in men. Results: MR analyses demonstrated a causal effect of serum E2 on eBMD and fracture risk. A 1 SD (or 9.6 pg/mL) genetically instrumented decrease in serum E2 levels was associated with a 0.38 SD decrease in eBMD (P value: 9.7 × 10-74) and an increased risk of any fracture (OR: 1.35; 95% CI: 1.18, 1.55), nonvertebral major osteoporotic fractures (OR: 1.75; 95% CI: 1.35, 2.27), and wrist fractures (OR: 2.27; 95% CI: 1.62, 3.16). These causal effects of serum E2 levels on fracture risk were robust in sensitivity analyses and remained unchanged in stratified analyses for age, body mass index, eBMD, smoking status, and physical activity. MR analyses revealed no evidence of a causal effect of T levels on fracture risk. Conclusion: Our findings provide evidence of a robust causal effect of serum E2, but not T, on fracture risk in men.

Developing confidence in basic prescribing skills during medical school: a longitudinal questionnaire study investigating the effects of a modified clinical pharmacology course.

PURPOSE: To investigate if increased focus on pharmacotherapy during medical school can increase students' confidence in basic prescribing skills, that is, performing medication reviews and writing medication discharge summaries. METHODS: In 2016, the clinical pharmacology course in medical school in Gothenburg, Sweden, was modified to facilitate the students' acquisition of prescribing skills, with (i) clarified learning outcomes; (ii) supply of a list of common drugs for self-completion; (iii) instructions to practice medication reviews/discharge summaries during the ward-based education; and (iv) a concluding compulsory seminar where the students were to present prescribing-related experiences from their ward-based attendance. Questionnaires were administered to students participating in the course before (2016; n = 101) and after (2017; n = 137) implementation of the modifications. Students were asked to grade their agreement from 1 (totally disagree) to 5 (totally agree) on statements related to their perceived confidence in basic prescribing skills. RESULTS: In all, 195 students returned the questionnaire (response rate 82%; median age 24 years; 68% female). Confidence was rated higher after the modifications were implemented, both regarding medication reviews and medication discharge summaries, after vs. before 3.6 ± 1.2 vs. 3.2 ± 1.0 (P = 0.024), and 4.3 ± 0.9 vs. 3.9 ± 1.1 (P = 0.008), respectively. The adjusted odds for being confident in performing these tasks were 1.49/1.36 times greater after the course modifications (P = 0.047/0.019). Perceived confidence in performing medication reviews/summary reports was positively correlated with numbers performed (P < 0.0001). CONCLUSIONS: Modifications of the clinical pharmacology course during medical school, focusing on students' training in pharmacotherapy, was associated with increased confidence of this core skill for a physician.

Genetic Determinants of Circulating Estrogen Levels and Evidence of a Causal Effect of Estradiol on Bone Density in Men.

Context: Serum estradiol (E2) and estrone (E1) levels exhibit substantial heritability. Objective: To investigate the genetic regulation of serum E2 and E1 in men. Design, Setting, and Participants: Genome-wide association study in 11,097 men of European origin from nine epidemiological cohorts. Main Outcome Measures: Genetic determinants of serum E2 and E1 levels. Results: Variants in/near CYP19A1 demonstrated the strongest evidence for association with E2, resolving to three independent signals. Two additional independent signals were found on the X chromosome; FAMily with sequence similarity 9, member B (FAM9B), rs5934505 (P = 3.4 × 10-8) and Xq27.3, rs5951794 (P = 3.1 × 10-10). E1 signals were found in CYP19A1 (rs2899472, P = 5.5 × 10-23), in Tripartite motif containing 4 (TRIM4; rs17277546, P = 5.8 × 10-14), and CYP11B1/B2 (rs10093796, P = 1.2 × 10-8). E2 signals in CYP19A1 and FAM9B were associated with bone mineral density (BMD). Mendelian randomization analysis suggested a causal effect of serum E2 on BMD in men. A 1 pg/mL genetically increased E2 was associated with a 0.048 standard deviation increase in lumbar spine BMD (P = 2.8 × 10-12). In men and women combined, CYP19A1 alleles associated with higher E2 levels were associated with lower degrees of insulin resistance. Conclusions: Our findings confirm that CYP19A1 is an important genetic regulator of E2 and E1 levels and strengthen the causal importance of E2 for bone health in men. We also report two independent loci on the X-chromosome for E2, and one locus each in TRIM4 and CYP11B1/B2, for E1.

Low Testosterone, but Not Estradiol, Is Associated With Incident Falls in Older Men: The International MrOS Study.

Fracture risk is determined by bone strength and the risk of falls. The relationship between serum sex steroids and bone strength parameters in men is well known, whereas the predictive value of sex steroids for falls is less studied. The aim of this study was to assess the associations between serum testosterone (T) and estradiol (E2) and the likelihood of falls. Older men (aged ≥65 years) from the United States (n = 1919), Sweden (n = 2495), and Hong Kong (n = 1469) participating in the Osteoporotic Fractures in Men Study had baseline T and E2 analyzed by mass spectrometry. Bioavailable (Bio) levels were calculated using mass action equations. Incident falls were ascertained every 4 months during a mean follow-up of 5.7 years. Associations between sex steroids and falls were estimated by generalized estimating equations. Fall rate was highest in the US and lowest in Hong Kong (US 0.50, Sweden 0.31, Hong Kong 0.12 fall reports/person/year). In the combined cohort of 5883 men, total T (odds ratio [OR] per SD increase = 0.88, 95% confidence interval [CI] 0.86-0.91) and BioT (OR = 0.86, 95% CI 0.83-0.88) were associated with incident falls in models adjusted for age and prevalent falls. These associations were only slightly attenuated after simultaneous adjustment for physical performance variables (total T: OR = 0.94, 95% CI 0.91-0.96; BioT: OR = 0.91, 95% CI 0.89-0.94). E2, BioE2, and sex hormone-binding globulin (SHBG) were not significantly associated with falls. Analyses in the individual cohorts showed that both total T and BioT were associated with falls in MrOS US and Sweden. No association was found in MrOS Hong Kong, and this may be attributable to environmental factors rather than ethnic differences because total T and BioT predicted falls in MrOS US Asians. In conclusion, low total T and BioT levels, but not E2 or SHBG, are associated with increased falls in older men. © 2017 American Society for Bone and Mineral Research.

The Bone Sparing Effects of 2-Methoxyestradiol Are Mediated via Estrogen Receptor-α in Male Mice.

2-Methoxyestradiol (2ME2), a metabolite of 17ß-estradiol (E2), exerts bone sparing effects in animal models. We hypothesized that the underlying mechanism is back conversion of 2ME2 to E2, which subsequently acts via estrogen receptor (ER)α. We measured serum E2 levels in orchidectomized wild-type (WT) mice treated with 2ME2 66.6 µg/d or placebo. In placebo-treated animals, E2 was below the detection limit. In 2ME2-treated mice, the serum E2 level was 4.97 ± 0.68 pg/mL. This corresponds to the level found in diesterus in cycling female mice. Next, we investigated bone parameters in orchidectomized WT and ERα knockout mice treated with 2ME2 or placebo for 35 days. 2ME2 (6.66 µg/d) preserved trabecular and cortical bone in WT mice. Trabecular volumetric-bone mineral density was 64 ± 20%, and trabecular bone volume/total volume was 60 ± 20% higher in the metaphyseal region of the femur in the 2ME2 group, compared with placebo (P < .01). Both trabecular number and trabecular thickness were increased (P < .01). Cortical bone mineral content in the diaphyseal region of the femur was 31 ± 3% higher in the 2ME2 group, compared with placebo (P < .001). This was due to larger cortical area (P < .001). Three-point bending showed an increased bone strength in WT 2ME2-treated animals compared with placebo (maximum load [Fmax] +19±5% in the 2ME2 group, P < .05). Importantly, no bone parameter was affected by 2ME2 treatment in ERα knockout mice. In conclusion, 2ME2 treatment of orchidectomized mice results in increased serum E2. ERα mediates the bone sparing effects of 2ME2. The likely mediator of this effect is E2 resulting from back conversion of 2ME2.

High-sensitivity CRP is an independent risk factor for all fractures and vertebral fractures in elderly men: the MrOS Sweden study.

Epidemiological studies have shown low-grade inflammation measured by high-sensitivity C-reactive protein (hs-CRP) to be associated with fracture risk in women. However, it is still unclear whether hs-CRP is also associated with fracture risk in men. We therefore measured serum levels of hs-CRP in 2910 men, mean age 75 years, included in the prospective population-based MrOS Sweden cohort. Study participants were divided into tertile groups based on hs-CRP level. Fractures occurring after the baseline visit were validated (average follow-up 5.4 years). The incidence for having at least one fracture after baseline was 23.9 per 1000 person-years. In Cox proportional hazard regression analyses adjusted for age, hs-CRP was related to fracture risk. The hazard ratio (HR) of fracture for the highest tertile of hs-CRP, compared with the lowest and the medium tertiles combined, was 1.48 (95% CI, 1.20-1.82). Multivariate adjustment for other risk factors for fractures had no major effect on the associations between hs-CRP and fracture. Results were essentially unchanged after exclusion of subjects with hs-CRP levels greater than 7.5 mg/L, as well as after exclusion of subjects with a first fracture within 3 years of follow-up, supporting that the associations between hs-CRP and fracture risk were not merely a reflection of a poor health status at the time of serum sampling. Femoral neck bone mineral density (BMD) was not associated with hs-CRP, and the predictive role of hs-CRP for fracture risk was essentially unchanged when femoral neck BMD was added to the model (HR, 1.37; 95% CI, 1.09-1.72). Exploratory subanalyses of fracture type demonstrated that hs-CRP was clearly associated with clinical vertebral fractures (HR, 1.61; 95% CI, 1.12-2.29). We demonstrate, using a large prospective population-based study, that elderly men with high hs-CRP have increased risk of fractures, and that these fractures are mainly vertebral. The association between hs-CRP and fractures was independent of BMD. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Association of SRD5A2 variants and serum androstane-3alpha,17beta-diol glucuronide concentration in Chinese elderly men.

BACKGROUND: Results of recent studies have demonstrated that genetic variants of the enzyme steroid 5α reductase type II (SRD5A2) are associated with serum concentrations of major androgen metabolites such as conjugates of androstane-3α,17ß-diol-glucuronide (3α-diol-G). However, this association was not consistently found among different ethnic groups. Thus, we aimed to determine whether the association with SRD5A2 genetic variations exists in a cohort of healthy Chinese elderly men, by examining 2 metabolite conjugates: androstane-3α,l7ß-diol-3-glucuronide (3α-diol-3G) and androstane-3α,17ß-diol-17-glucuronide (3α-diol-17G). METHODS: We used GC-MS and LC-MS to measure serum sex steroid concentrations, including testosterone and dihydrotestosterone, and 3α-diol-3G and 3α-diol-17G in 1182 Chinese elderly men age 65 and older. Genotyping of the 3 SRD5A2 tagSNPs [rs3731586, rs12470143, and rs523349 (V89L)] was performed by using melting-temperature-shift allele-specific PCR. RESULTS: The well-described SRD5A2 missense variant rs523349 (V89L) was modestly associated with the 3α-diol-17G concentration (P = 0.040). On the other hand, SNP rs12470143 was found to be significantly correlated with 3α-diol-3G concentration (P = 0.021). Results of haplotype analysis suggested that the presence of an A-C-G haplotype leads to an increased 3α-diol-3G concentration, a finding consistent with results of single SNP analysis. CONCLUSIONS: The genetic variation of SRD5A2 is associated with circulating 3α-diol-3G and 3α-diol-17G concentrations in Chinese elderly men. In addition, we showed that SRD5A2 haplotypic association, rather than a single SNP alone, might be a better predictor of the 3α-diol-G concentration. Thus, the effect of either the haplotype itself or of other ungenotyped SNPs in linkage disequilibrium with the haplotype is responsible for the interindividual variation of 3α-diol-G.

Characteristics of primary health care units with focus on drug information from the pharmaceutical industry and adherence to prescribing objectives: a cross-sectional study.

BACKGROUND: Adherence to prescribing guidelines varies between primary health care units. The aim of the present study was to investigate correlations between characteristics of primary health care units and adherence to prescribing objectives for rational drug use with focus on drug information from the pharmaceutical industry. METHODS: A cross-sectional study was performed in all 25 primary health care units in Göteborg, Sweden. A questionnaire on characteristics of practice settings [(i) size of unit, (ii) profession of head, (iii) use of temporary physicians, (iv) drug information from the pharmaceutical industry, (v) producer-independent drug information, and (vi) education on prescribing for newly employed physicians] was sent to the heads of the units. A national sales register for prescribed drugs (Xplain) was used for evaluation of adherence to the six regional prescribing objectives concerning proton pump inhibitors (PPIs), angiotensin converting enzyme inhibitors (ACEIs), statins and antidepressants. RESULTS: Twenty-two out of 25 primary health care units responded to the questionnaire (response rate 88%). A physician as head and presence of producer-independent drug information was positively correlated with adherence to the prescribing objectives (median number of prescribing objectives adhered to (25th - 75th percentile): 2.5 (1-3.25) vs 1 (0-2), P = 0.013; 2 (1-3) vs 0, P = 0.043, respectively. Presence of drug information from the pharmaceutical industry and education on prescribing for newly employed physicians was negatively associated with adherence to the prescribing objectives: 1 (0-2) vs 3.5 (2.25-4.75), P = 0.005; 1 (0-2) vs 3 (1.5-4), P = 0.034, respectively. CONCLUSION: Several characteristics of the primary health care units correlated with adherence to prescribing objectives for rational drug use. Further research on this topic is needed and would constitute valuable information for health care decision makers.

Association of genetic variations in aromatase gene with serum estrogen and estrogen/testosterone ratio in Chinese elderly men.

BACKGROUND: Single nucleotide polymorphism (SNP) rs2470152 of the gene CYP19A1 is associated with serum estradiol (E2) levels in Caucasian men. However, it remains to be verified if rs2470152 is the sole determinant accounting for the association. We determined whether 2 CYP19A1 SNPs tagging different haploblocks (rs2470152 and rs2899470) are associated with sex steroid levels in Chinese men. METHOD: Serum sex steroid level including E2, estrone (E1) and testosterone (T), of 1402 Chinese men aged > or = 65 years were analyzed. Genotyping of the two CYP19A1 SNPs was performed using Tm-shift allele-specific PCR. RESULTS: SNP rs2899470 was significantly associated with serum E2, E1 levels and E2/T ratio (p<0.001). However, SNP rs2470152 was only modestly associated with E2/T ratio (p=0.023). Analysis of haplotype showed a significant association between C-G, T-T haplotype with serum E2/T ratio (p=0.019 and p=1 x 10(-5), respectively). Similarly, E2 levels was also associated the T-T and T-G haplotypes (p=1 x 10(-5)). CONCLUSION: The genetic variation of CYP19A1 was associated with circulating estrogen levels in Chinese elderly men. In addition, it revealed that haplotype of rs2899470 and rs2470152, rather than rs2899470 alone, was a better indicator for the serum E2/T ratio and E2 levels.

Montelukast and psychiatric disorders in children.

PURPOSE: A signal has been raised concerning montelukast and adverse drug reactions (ADRs) in children. The purpose of the present study was to evaluate psychiatric ADRs during treatment with montelukast in children. METHODS: We analyzed all reports of psychiatric disorders during treatment with montelukast in children (<18 years) in the Swedish ADR database SWEDIS (1998-2007). The Bayesian Confidence Propagation Neural Network (BCPNN) method was used to screen for disproportional reporting rates of these reactions. An information component (IC) with a positive 95% lower confidence limit indicates a statistically significant disproportionality between the expected and the reported rate for a drug and an ADR. RESULTS: A total of 48 reports of psychiatric disorders in children during treatment with montelukast were found in SWEDIS. Reports appeared every year after registration. Psychiatric disorders reported more than once included nightmares (n = 15), unspecified anxiety (n = 11), aggressiveness (n = 11), sleep disorders (n = 10), insomnia (n = 3), irritability (n = 3), hallucination (n = 3), hyperactivity (n = 3), and personality disorder (n = 2). In 23 reports (48%), the child experiencing psychiatric ADRs was < or = 3 years old. Time from exposure to ADR was indicated in 35 reports. In 28 of these (80%), the time from exposure to ADR was less than 1 week. A statistical signal for psychiatric disorders appeared in the fourth quarter of 1998 (three reports, IC-value: 2.34, 95% lower confidence limit: 0.62). CONCLUSIONS: Psychiatric ADRs can occur during montelukast treatment in children, indicating that attention to this is essential. Further studies are needed to establish the magnitude of the problem.

Genetic variations in sex steroid-related genes as predictors of serum estrogen levels in men.

CONTEXT: The risk of many conditions, including prostate cancer, breast cancer, and osteoporosis, is associated with serum levels of sex steroids. OBJECTIVE: The aim of the study was to identify genetic variations in sex steroid-related genes that are associated with serum levels of estradiol (E2) and/or testosterone in men. DESIGN: Genotyping of 604 single nucleotide polymorphisms in 50 sex steroid-related candidate genes was performed in the Gothenburg Osteoporosis and Obesity Determinants (GOOD) study (n = 1041 men; age, 18.9 +/- 0.6 yr). Replications of significant associations were performed in the Osteoporotic Fractures in Men (MrOS) Sweden study (n = 2568 men; age, 75.5 +/- 3.2 yr) and in the MrOS US study (n = 1922 men; age, 73.5 +/- 5.8 yr). Serum E2, testosterone, and estrone (E1) levels were analyzed using gas chromatography/mass spectrometry. RESULTS: The screening in the GOOD cohort identified the single nucleotide polymorphism rs2470152 in intron 1 of the CYP19 gene, which codes for aromatase, responsible for the final step of the biosynthesis of E2 and E1, to be most significantly associated with serum E2 levels (P = 2 x 10(-6)). This association was confirmed both in the MrOS Sweden study (P = 9 x 10(-7)) and in the MrOS US study (P = 1 x 10(-4)). When analyzed in all subjects (n = 5531), rs2470152 was clearly associated with both E2 (P = 2 x 10(-14)) and E1 (P = 8 x 10(-19)) levels. In addition, this polymorphism was modestly associated with lumbar spine BMD (P < 0.01) and prevalent self-reported fractures (P < 0.05). CONCLUSIONS: rs2470152 of the CYP19 gene is clearly associated with serum E2 and E1 levels in men.

IL6 and IL1B polymorphisms are associated with fat mass in older men: the MrOS Study Sweden.

There is growing evidence that immune functions are linked to the regulation of body fat. Our studies of knockout mice indicate that both endogenous interleukin (IL)-6 and IL-1 can suppress mature-onset obesity. We now investigated whether four common polymorphisms of the IL6 and IL1 systems are associated with the fat mass measured with dual-energy X-ray absorptiometry (DXA) in elderly men (n = 3,014). The study subjects were from the Swedish part of the MrOS multicenter population study and 69-81 years of age. The IL6 -174 G>C (Minor allele frequency (MAF) = 48%) gene promoter polymorphism was associated with the primary outcome total fat mass (P = 0.006) and regional fat masses, but not with lean body mass. The IL1B -31T>C (MAF = 34%) polymorphism was also associated with total fat (P = 0.007) and regional fat masses, but not lean body mass. The IL-1 receptor antagonist (IL-1ra) gene (IL1RN) +2018 T>C (MAF = 27%) polymorphism (in linkage disequilibrium (LD) with a well-studied variable number tandem repeat of 86 base pair (bp)) and IL1B +3953 C>T (MAF = 26%) polymorphism were not associated with total fat mass. In conclusion, the IL-1 and IL-6 systems, shown to suppress mature-onset obesity in experimental animals, contain gene polymorphisms that are associated with fat, but not lean, mass in elderly men.

The COMT val158met polymorphism is associated with prevalent fractures in Swedish men.

INTRODUCTION: Sex steroids are important for growth and maintenance of the skeleton. Catechol-O-methyltransferase (COMT) is an estrogen degrading enzyme. The COMT val158met polymorphism results in a 60-75% difference in enzyme activity between the val (high activity=H) and met (low activity=L) variants. We have previously reported that this polymorphism is associated with bone mineral density (BMD) in young men. The aim of this study was to investigate associations between COMT val158met, BMD and fractures in elderly men. METHODS: Population-based study of Swedish men 75.4, SD 3.2, years of age. Fractures were reported using standardized questionnaires. Fracture and genotype data were available from 2,822 individuals. RESULTS: Total number of individuals with self-reported fracture was 989 (35.0%). Prevalence of >or=1 fracture was 37.2% in COMT(LL), 35.7% in COMT(HL) and 30.4% in COMT(HH) (p<0.05). Early fractures (50 years of age). The OR for fracture of the non-weight bearing skeleton in COMT(HH) compared with COMT(LL+HL) was 0.74 (95% CI 0.59-0.92). No associations between COMT val158met and BMD were found in this cohort of elderly men. CONCLUSIONS: The COMT val158met polymorphism is associated with life time fracture prevalence in elderly Swedish men. This association is mainly driven by early fractures (

Association between physical activity and BMD in young men is modulated by catechol-O-methyltransferase (COMT) genotype: the GOOD study.

UNLABELLED: In this large population-based study in young men, we show that the COMT val158met polymorphism modulates the association between physical activity, aBMD (DXA), and trabecular vBMD (pQCT). INTRODUCTION: Peak BMD is an important predictor of future risk of osteoporosis and is largely determined by genetic factors but also by environmental factors, among which physical activity (PA) is a strong contributor. Estrogens are believed to influence the mechanical strain signal generated by bones subjected to mechanical loading. Catechol-O-methyltransferase (COMT) is involved in the degradation of estrogens. A functional polymorphism in the COMT gene (val158met), results in a 60-75% difference in enzyme activity between the val (high activity = H) and met (low activity = L) variants. The aim of this study was to determine if the COMT val158met polymorphism modulates the association between PA and BMD in young men. MATERIALS AND METHODS: The Gothenburg Osteoporosis and Obesity Determinants (GOOD) study consists of 1068 men (age, 18.9 +/- 0.6 yr). Areal BMD (aBMD) was measured by DXA, whereas cortical and trabecular volumetric BMD (vBMD) were measured by pQCT. Study subjects were genotyped and classified as COMT(LL), COMT(HL), or COMT(HH). The amount (h/wk) of PA was determined through questionnaires. RESULTS: Using a linear regression model (including age, height, weight, smoking, and calcium intake as covariates), significant interactions between the COMT genotype and PA were seen for aBMD at all sites and for trabecular vBMD in both the radius and the tibia. The difference in adjusted aBMD and trabecular vBMD between high (>or=4 h/wk) and low PA (<4 h/wk) was greater in COMT(LL) subjects than in subjects homozygous for the COMT(HH) (total body aBMD: COMT(LL) 4.2% versus COMT(HH) 1.5%, p = 0.02; lumbar spine aBMD: COMT(LL) 7.8% versus COMT(HH) 3.9%, p = 0.04; tibia trabecular vBMD: COMT(LL) 7.1% versus COMT(HH) 1.0%, p < 0.01). The COMT polymorphism was associated with aBMD, at all sites and with trabecular vBMD in the low-PA subjects, but not in their high-PA counterparts. CONCLUSIONS: We show that the COMT val158met polymorphism modulates the association between PA, aBMD, and trabecular vBMD, suggesting that this polymorphism is of importance for BMD in subjects with a low level of PA.

Serum levels of specific glucuronidated androgen metabolites predict BMD and prostate volume in elderly men.

UNLABELLED: Androgens are important regulators of bone and prostate health in elderly men. The role of serum levels of glucuronidated androgen metabolites as predictors of BMD and prostate volume in men is unclear. We show that specific glucuronidated androgen metabolites predict BMD and prostate volume in elderly men. INTRODUCTION: Androgens are important regulators of bone and prostate health in elderly men. Local synthesis and degradation of androgens are likely to be important parameters of biological action of androgens in androgen-responsive tissues. The aim of this study was to determine the role of serum levels of glucuronidated androgen metabolites as predictors of BMD and prostate volume in elderly men. MATERIALS AND METHODS: A subsample of the population-based Swedish part of the MrOS study (n = 631, average age = 75.9 years) was investigated. Bone parameters were measured using DXA. Serum levels of total testosterone (T) and dihydrotestosterone (DHT) were measured by gas chromatography/mass spectroscopy (GC-MS); androstane-3alpha,17beta-diol-3glucuronide (3G) and androstane-3alpha,17beta-diol-17glucuronide (17G) were measured by liquid chromatography/mass spectroscopy. Prostate volume (n = 159) was measured by transrectal ultrasound. RESULTS: The general pattern is that two of the glucuronidated androgen metabolites, namely 17G and 3G, are stronger positive predictors of BMD than the bioactive androgens (T and DHT). In addition, 17G is a clear positive predictor of prostate volume, explaining 4.5% of the variance in prostate volume, whereas the bioactive androgens do not display any association with prostate volume. CONCLUSIONS: Serum levels of specific glucuronidated androgen metabolites predict BMD and prostate volume in elderly men. Future studies should determine if the glucuronidated androgen metabolites also reflect other biological correlates of androgenic activity, including prostate cancer, and if low levels might be a marker of general androgen deficiency in men.