| 311. |
- Kristjansdottir, Hallgerdur Lind, et al.
(author)
-
High Serum Serotonin Predicts Increased Risk for Hip Fracture and Nonvertebral Osteoporotic Fractures : The MrOS Sweden Study
- 2018
-
In: Journal of Bone and Mineral Research. - : Wiley. - 0884-0431. ; 33:9, s. 1560-1567
-
Journal article (peer-reviewed)abstract
- Because several studies have implicated serotonin as a regulator of bone mass, we here explore its potential association on fracture risk and falls, as on bone mineral density (BMD) and muscle strength, in humans. Serum levels of serotonin were analyzed in 950 men (aged 69 to 81 years), participating in the Gothenburg part of the population-based study MrOS Sweden. Men taking selective serotonin reuptake inhibitors (SSRIs) had a mean value of 31.2 μg/L compared with 159.4 μg/L in those not taking SSRIs. SSRI users were excluded from further analysis. During 10-year follow-up, 224 men exhibited fractures, including 97 nonvertebral osteoporotic fractures (57 hip fractures), and 86 vertebral fractures. Serotonin was associated with hip fracture in linear analysis (hazard ratio [HR] = 1.27, 95% confidence interval [CI] 1.03–1.58) and to all fractures in a nonlinear manner, when quintiles of serotonin was included in quadratic terms (HR = 1.12, 95% CI 1.04–1.21). Men in serotonin quintile 5 had, in multivariable analysis, a HR of 2.30 (95% CI 1.31–4.02) for hip fracture and 1.82 (95% CI 1.17–2.85) for nonvertebral fractures compared with men in quintiles 1 to 4. Men in quintile 1 had, in multivariable analysis, a HR of 1.76 (95% CI 1.03–2.99) for nonvertebral fractures compared with men in quintiles 2 to 4. No association was found with vertebral fractures. Individuals in serotonin quintile 1 had higher prevalence of falls compared with quintiles 2 to 5 (odds ratio = 1.90, 95% CI 1.26–2.87). Serotonin was positively associated with hand-grip strength (r = 0.08, p = 0.02) and inversely with hip BMD (r = −0.10, p = 0.003). To assess the association between SSRIs and falls and fractures, the total MrOS Sweden cohort was examined (n = 3014). SSRI users (n = 90) had increased prevalence of falls (16% versus 33%, p = 0.0001) and increased rate of incident fractures (28.0 versus 44.7 per 1000 person-years, p = 0.018). We present novel data showing that high levels of serotonin predict an increased risk for hip fracture and nonvertebral osteoporotic fractures.
|
|
| 312. |
- Kugelberg, Maria, et al.
(author)
-
Glucocorticoid eye drops inhibit growth in the newborn rabbit.
- 2005
-
In: Acta paediatrica (Oslo, Norway : 1992). - 0803-5253. ; 94:8, s. 1096-101
-
Journal article (peer-reviewed)abstract
- AIM: To investigate if postoperative treatment with dexamethasone eye drops has the capacity to affect longitudinal growth in newborn rabbits. METHODS: Thirty-four male and female rabbits had clear lens extraction performed in one eye at 3 wk of age and were then treated either intensively (group 1) or less intensively (group 2) with de-escalating doses of dexamethasone eye drops for 8 wk (average doses 0.27 and 0.10 mg/kg body weight/day, respectively). The control group (group 3) received vehicle eye drops only. Body weight and crown-rump length were recorded every week. After 8 wk of treatment, all rabbits were killed and the left femur was measured. RESULTS: Rabbits treated with dexamethasone eye drops gained weight slower (711+/-42 and 989+/-153 g weight increase for groups 1 and 2, respectively) than control animals (group 3; 1224+/-87 g weight increase; p<0.001 vs group 1, p<0.01 vs group 2). Longitudinal growth, determined as increase in crown-rump and femur lengths, was impaired by dexamethasone eye drops in a dose-dependent way. Crown-rump length increased by 8.25+/-0.86, 10.90+/-1.19 and 15.35+/-1.31 cm in groups 1, 2 and 3, respectively (p<0.001 for all comparisons). At endpoint, i.e. after 8 wk of treatment, the average femur length was 6.36+/-0.21, 7.39+/-0.27 and 8.37+/-0.28 cm in groups 1, 2 and 3, respectively (p<0.001 for all comparisons). CONCLUSION: Dexamethasone, administered topically as eye drops, has systemic effects and impairs longitudinal growth in young rabbits. Therefore, we propose that growth should be closely monitored in all children intensively treated with glucocorticoid eye drops.
|
|
| 313. |
- Kugelberg, Maria, et al.
(author)
-
Reduced bone mineral density and radial bone growth in young rabbits treated with dexamethasone eye drops.
- 2005
-
In: Hormone research. - : S. Karger AG. - 0301-0163. ; 63:4, s. 165-70
-
Journal article (peer-reviewed)abstract
- OBJECTIVE: To investigate the effect of dexamethasone eye drops on bone metabolism in newborn rabbits. METHODS: Thirty-four 3-week-old rabbits had unilateral clear lens extraction and were randomized into three groups. Postoperatively, group 1 received high-dose and group 2 low-dose dexamethasone eye drops (average doses 0.27 and 0.10 mg/kg body weight/day, respectively). These rabbits also received a postoperative subconjunctival injection of betamethasone. Group 3 (control) received vehicle eye drops only. After 8 weeks of treatment, all animals were killed and the left femurs were isolated and subjected to peripheral quantitative computerized tomography (pQCT) and dual X-ray absorptiometry (DXA) analyses. RESULTS: DXA showed that rabbits treated with either a high or low dose of dexamethasone eye drops had significantly reduced areal bone mineral density (BMD), area and total bone mineral content (BMC) of the femur. Measurements with pQCT demonstrated a dose-dependent reduction in cortical BMC, cortical volumetric BMD and cortical area. These effects were associated with an inhibition of radial femur growth, cortical thickness and periosteal and endosteal circumferences. CONCLUSION: Dexamethasone eye drops have systemic effects affecting several bone parameters in young rabbits. Any long-term systemic effects of ocular glucocorticoids need to be further studied.
|
|
| 314. |
- Kwan, Johnny S H, et al.
(author)
-
Meta-analysis of genome-wide association studies identifies two loci associated with circulating osteoprotegerin levels.
- 2014
-
In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:24, s. 6684-93
-
Journal article (peer-reviewed)abstract
- Osteoprotegerin (OPG) is involved in bone homeostasis and tumor cell survival. Circulating OPG levels are also important biomarkers of various clinical traits, such as cancers and atherosclerosis. OPG levels were measured in serum or in plasma. In a meta-analysis of genome-wide association studies in up to 10,336 individuals from European and Asian origin, we discovered that variants >100 Kb upstream of the TNFRSF11B gene encoding OPG and another new locus on chromosome 17q11.2 were significantly associated with OPG variation. We also identified a suggestive locus on chromosome 14q21.2 associated with the trait. Moreover, we estimated that over half of the heritability of OPG levels could be explained by all variants examined in our study. Our findings provide further insight into the genetic regulation of circulating OPG levels.
|
|
| 315. |
- Kwan, Tony, et al.
(author)
-
Tissue effect on genetic control of transcript isoform variation.
- 2009
-
In: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 5:8
-
Journal article (peer-reviewed)abstract
- Current genome-wide association studies (GWAS) are moving towards the use of large cohorts of primary cell lines to study a disease of interest and to assign biological relevance to the genetic signals identified. Here, we use a panel of human osteoblasts (HObs) to carry out a transcriptomic survey, similar to recent studies in lymphoblastoid cell lines (LCLs). The distinct nature of HObs and LCLs is reflected by the preferential grouping of cell type-specific genes within biologically and functionally relevant pathways unique to each tissue type. We performed cis-association analysis with SNP genotypes to identify genetic variations of transcript isoforms, and our analysis indicates that differential expression of transcript isoforms in HObs is also partly controlled by cis-regulatory genetic variants. These isoforms are regulated by genetic variants in both a tissue-specific and tissue-independent fashion, and these associations have been confirmed by RT-PCR validation. Our study suggests that multiple transcript isoforms are often present in both tissues and that genetic control may affect the relative expression of one isoform to another, rather than having an all-or-none effect. Examination of the top SNPs from a GWAS of bone mineral density show overlap with probeset associations observed in this study. The top hit corresponding to the FAM118A gene was tested for association studies in two additional clinical studies, revealing a novel transcript isoform variant. Our approach to examining transcriptome variation in multiple tissue types is useful for detecting the proportion of genetic variation common to different cell types and for the identification of cell-specific isoform variants that may be functionally relevant, an important follow-up step for GWAS.
|
|
| 316. |
- Kwok, T, et al.
(author)
-
ACE inhibitor use was associated with lower serum dehydroepiandrosterone concentrations in older men.
- 2010
-
In: Clinica chimica acta. - : Elsevier BV. - 1873-3492 .- 0009-8981. ; 411:15-16, s. 1122-5
-
Journal article (peer-reviewed)abstract
- CONTEXT: Angiotensin converting enzyme (ACE) activity may influence the production of adrenal androgen precursors and testosterone. Use of ACE inhibitors may therefore have an influence on serum sex hormone concentrations in older men. DESIGN AND METHODS: 1486 out of 2,000 community-dwelling Chinese men aged 65years who participated in a cohort study were randomly selected to have archived fasting morning serum analyzed for androgen precursors and sex hormones. DNA was extracted from whole blood and analyzed for ACE gene I/D polymorphism. RESULTS: Subjects with the ACE gene D allele (higher ACE activity) had higher serum dehydroepiandrosterone (DHEA) sulphate and DHEA than those with I/I genotype (P=0.014 and 0.018 respectively, Mann Whitney test). These differences were not significant after Bonferroni correction. Among those with history of hypertension, but without diabetes mellitus or cardiac failure, users of ACE inhibitors had significantly lower serum DHEA (median 1.78 versus 1.49ng/ml in non-users, P=0.0074, Mann Whitney test) and also tended to have lower serum androstenedione and androst-5-ene-3beta,17beta-diol (0.68 versus 0.72ng/ml in non-users; 552.4 versus 624.1pg/ml respectively, both P values <0.05). Serum testosterone and estradiol were not significantly changed. CONCLUSIONS: ACE inhibitor use was associated with lower serum DHEA in older men.
|
|
| 317. |
- Labrie, Fernand, et al.
(author)
-
Comparable amounts of sex steroids are made outside the gonads in men and women: Strong lesson for hormone therapy of prostate and breast cancer.
- 2009
-
In: The Journal of steroid biochemistry and molecular biology. - : Elsevier BV. - 0960-0760. ; 113:1-2, s. 52-6
-
Journal article (peer-reviewed)abstract
- The objective of this study was comparison of circulating androgens and their metabolites as well as estrogens measured for the first time by a validated mass spectrometry technology in 60-80-year-old men and women of comparable age. Castration in men (n=34) reduces the total androgen pool by only about 60% as indicated by the decrease in the serum levels of the glucuronide metabolites of androgens compared to intact men (n=1302). Such data are in agreement with the 50 to 75% decrease in intraprostatic dihydrotestosterone (DHT) concentration after castration. Most interestingly, the same amounts of androgens and estrogens are found in postmenopausal women (n=369) and castrated men of comparable age. The most significant therapeutic implication of these findings is the absolute need to add a pure (nonsteroidal) antiandrogen to castration in men with prostate cancer in order to block the action of the 25 to 50% DHT left in the prostate after castration. Not adding an antiandrogen to castration in men treated for prostate cancer is equivalent to not prescribing a blocker of estrogens in women suffering from breast cancer because they are postmenopausal and have low circulating estradiol.
|
|
| 318. |
- Lagerholm, Sofia, et al.
(author)
-
Genetic regulation of bone traits is influenced by sex and reciprocal cross in F(2) progeny from GK and F344 rats.
- 2009
-
In: Journal of bone and mineral research. - : Wiley. - 1523-4681 .- 0884-0431. ; 24:6, s. 1066-74
-
Journal article (peer-reviewed)abstract
- A genome-wide linkage analysis to identify quantitative trait loci (QTLs) for bone phenotypes was performed in an F(2) intercross of inbred spontaneously type 2 diabetic GK and normoglycemic F344 rats (108 males and 98 females). The aim of the study was to locate genome regions with candidate genes affecting trabecular and cortical bone and to investigate the effects of sex and reciprocal cross. pQCT was used to determine tibial bone phenotypes in the F(2) rats, comprising reciprocal crosses with divergent mitochondrial (mt) DNA. Sex and reciprocal cross-separated QTL analyses were performed followed by assessment of specific interactions. Four genome-wide significant QTLs linked to either cortical vBMD, tibia length, body length, or metaphyseal area were identified in males on chromosomes (chr) 1, 8, and 15. In females, three significant QTLs linked to cortical BMC or metaphyseal total vBMD were identified on chr 1 and 2. Several additional suggestive loci for trabecular and cortical traits were detected in both males and females. Four female-specific QTLs on chr 2, 3, 5, and 10 and four reciprocal cross-specific QTLs on chr 1, 10, and 18 were identified, suggesting that both sex and mt genotype influence the expression of bone phenotypes.
|
|
| 319. |
- Lagerquist, Marie, et al.
(author)
-
Androgens and the skeleton.
- 2005
-
In: Minerva endocrinologica. - 0391-1977. ; 30:1, s. 15-25
-
Journal article (peer-reviewed)abstract
- Loss of estrogens or androgens causes bone loss by increasing the rate of bone remodeling, and also causes an imbalance between resorption and formation by prolonging the lifespan of osteoclasts and shortening the lifespan of osteoblasts. Conversely, treatment with androgens, as well as estrogens, maintains cancellous bone mass and integrity, regardless of age or sex. Both androgens, via the androgen receptor (AR), and estrogens, via the estrogen receptors (ERs) can exert these effects, but the relative contribution of these 2 pathways remains uncertain. Androgens, like estrogens, stimulate endochondral bone formation at the start of puberty, whereas they induce epiphyseal closure at the end of puberty, thus, they have a biphasic effect. Androgen action on the growth plate is, however, clearly mediated via aromatization into estrogens and interaction with ER alpha. Androgens increase, while estrogens decrease radial growth. This differential effect of the sex steroids may be important because bone strength in males seems to be determined by higher periosteal bone formation and, therefore, greater bone dimensions. Experiments in mice suggest that both the AR and ER alpha pathways are involved in androgen action on radial bone growth. ER beta may mediate growth-limiting effects of estrogens in the female but does not seem to be involved in the regulation of bone size in males. In conclusion, androgens may protect men against osteoporosis via maintenance of cancellous bone mass and expansion of cortical bone. This androgen action on bone is mediated by the AR and ER alpha.
|
|
| 320. |
- Lagerquist, Marie K, et al.
(author)
-
Acute fat loss does not affect bone mass
- 2021
-
In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
-
Journal article (peer-reviewed)abstract
- Obesity has previously been thought to protect bone since high body weight and body mass index are associated with high bone mass. However, some more recent studies suggest that increased adiposity negatively impacts bone mass. Here, we aimed to test whether acute loss of adipose tissue, via adipocyte apoptosis, alters bone mass in age-related obese mice. Adipocyte apoptosis was induced in obese male FAT-ATTAC mice through AP20187 dimerizer-mediated activation of caspase 8 selectively in adipocytes. In a short-term experiment, dimerizer was administered to 5.5 month-old mice that were terminated 2 weeks later. At termination, the total fat mass weighed 58% less in dimerizer-treated mice compared with vehicle-treated controls, but bone mass did not differ. To allow for the detection of long-term effects, we used 9-month-old mice that were terminated six weeks after dimerizer administration. In this experiment, the total fat mass weighed less (- 68%) in the dimerizer-treated mice than in the controls, yet neither bone mass nor biomechanical properties differed between groups. Our findings show that adipose tissue loss, despite the reduced mechanical loading, does not affect bone in age-related obese mice. Future studies are needed to test whether adipose tissue loss is beneficial during more severe obesity.
|
|
