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Melhus, Håkan
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Publications (10 of 131) Show all publications
Larsson, S. C., Melhus, H. & Michaëlsson, K. (2018). Circulating Serum 25-Hydroxyvitamin D Levels and Bone Mineral Density: Mendelian Randomization Study. Journal of Bone and Mineral Research, 33(5), 840-844
Open this publication in new window or tab >>Circulating Serum 25-Hydroxyvitamin D Levels and Bone Mineral Density: Mendelian Randomization Study
2018 (English)In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 33, no 5, p. 840-844Article in journal (Refereed) Published
Abstract [en]

There is considerable discussion of the importance for increased serum 25‐hydroxyvitamin D (S‐25OHD) concentration associated with adequacy for bone health. Accordingly, whether long‐term high S‐25OHD concentration in general positively affects bone mineral density (BMD) is uncertain. We used a Mendelian randomization design to determine the association between genetically increased S‐25OHD concentrations and BMD. Five single‐nucleotide polymorphisms (SNPs) in or near genes encoding enzymes and carrier proteins involved in vitamin D synthesis or metabolism were used as instrumental variables to genetically predict 1 standard deviation increase in S‐25OHD concentration. Summary statistics data for the associations of the S‐25OHD‐associated SNPs with dual‐energy X‐ray absorptiometry (DXA)‐derived femoral neck and lumbar spine BMD were obtained from the Genetic Factors for Osteoporosis (GEFOS) Consortium (32,965 individuals) and ultrasound‐derived heel estimated BMD from the UK Biobank (142,487 individuals). None of the SNPs were associated with BMD at Bonferroni‐corrected significance level, but there was a suggestive association between rs6013897 near CYP24A1 and femoral neck BMD (p = 0.01). In Mendelian randomization analysis, genetically predicted 1 standard deviation increment of S‐25OHD was not associated with higher femoral neck BMD (SD change in BMD 0.02; 95% confidence interval [CI] –0.03 to 0.07; p = 0.37), lumbar spine BMD (SD change in BMD 0.02; 95% CI –0.04 to 0.08; p = 0.49), or estimated BMD (g/cm2 change in BMD –0.03; 95% CI –0.05 to –0.01; p = 0.02). This study does not support a causal association between long‐term elevated S‐25OHD concentrations and higher BMD in generally healthy populations. These results suggest that more emphasis should be placed on the development of evidence‐based cut‐off points for vitamin D inadequacy rather than a general recommendation to increase S‐25OHD.

Keywords
Bone Mineral Density, Mendelian Randomization, Osteoporosis, Single-Nucleotide Polymorphisms, Vitamin D
National Category
Orthopaedics Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-344294 (URN)10.1002/jbmr.3389 (DOI)000432006800010 ()29338102 (PubMedID)
Funder
Forte, Swedish Research Council for Health, Working Life and Welfare
Available from: 2018-03-06 Created: 2018-03-06 Last updated: 2018-08-10Bibliographically approved
Kempen, T. & Melhus, H. (2018). Correspondence: A Trial of Blood-Pressure Reduction in Black Barbershops [Letter to the editor]. New England Journal of Medicine, 379(2), 199-199
Open this publication in new window or tab >>Correspondence: A Trial of Blood-Pressure Reduction in Black Barbershops
2018 (English)In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 379, no 2, p. 199-199Article in journal, Letter (Other academic) Published
National Category
General Practice
Identifiers
urn:nbn:se:uu:diva-365261 (URN)10.1056/NEJMc1806026 (DOI)000438249800020 ()29998726 (PubMedID)
Available from: 2018-11-12 Created: 2018-11-12 Last updated: 2018-11-12Bibliographically approved
Michaëlsson, K., Wolk, A., Warensjö, E., Melhus, H. & Byberg, L. (2018). Intake of milk or fermented milk combined with fruit and vegetable consumption in relation to hip fracture rates: A cohort study of Swedish women.. Journal of Bone and Mineral Research, 33(3), 449-457
Open this publication in new window or tab >>Intake of milk or fermented milk combined with fruit and vegetable consumption in relation to hip fracture rates: A cohort study of Swedish women.
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2018 (English)In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 33, no 3, p. 449-457Article in journal (Refereed) Published
Abstract [en]

Milk products may differ in pro-oxidant properties and their effects on fracture risk could potentially be modified by the intake of foods with antioxidant activity. In the population-based Swedish Mammography Cohort study, we aimed to determine how milk and fermented milk combined with fruit and vegetable consumption are associated with hip fracture. Women born 1914-1948 (n=61 240) answered food frequency and lifestyle questionnaires in 1987-1990 and 38 071 women contributed with updated information in 1997. During a mean follow-up of 22 years, 5827 women had a hip fracture (ascertained via official register data). Compared with a low intake of milk (<1 glass/day) and a high intake of fruits and vegetables (≥5 servings/day), a high intake of milk (≥3 glasses/day) with a concomitant low intake of fruits and vegetables (<2 servings/day) resulted in a HR of 2.49 (95% CI, 2.03-3.05). This higher hip fracture rate among high consumers of milk was only modestly attenuated with a concomitant high consumption of fruit and vegetables (HR 2.14; 95% CI 1.69-2.71). The combination of fruits and vegetables with fermented milk (yogurt or soured milk) yielded a different pattern with lowest rates of hip fracture in high consumers: HR 0.81 (95% CI, 0.68-0.97) for ≥2 servings/day of fermented milk and ≥5 servings/day of fruits and vegetables compared with low consumption of both fruit and vegetables and fermented milk. We conclude that the amount and type of dairy products as well as fruit and vegetable intake are differentially associated with hip fracture rates in women.

Keywords
dairy, fruit, hip fracture, milk, vegetables
National Category
Orthopaedics
Identifiers
urn:nbn:se:uu:diva-334436 (URN)10.1002/jbmr.3324 (DOI)000426731100011 ()29083056 (PubMedID)
Funder
Swedish Research Council, 2011-2427
Available from: 2017-11-23 Created: 2017-11-23 Last updated: 2018-08-24Bibliographically approved
Kaluza, J., Harris, H., Melhus, H., Michaëlsson, K. & Wolk, A. (2018). Questionnaire-Based Anti-Inflammatory Diet Index as a Predictor of Low-Grade Systemic Inflammation.. Antioxidants and Redox Signaling, 28(1), 78-84
Open this publication in new window or tab >>Questionnaire-Based Anti-Inflammatory Diet Index as a Predictor of Low-Grade Systemic Inflammation.
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2018 (English)In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 28, no 1, p. 78-84Article in journal (Refereed) Published
Abstract [en]

There is accumulating evidence that diet may be associated with markers of inflammation. We have evaluated if an empirically developed questionnaire-based Anti-Inflammatory Diet Index (AIDI) may predict low-grade systemic chronic inflammation in a Nordic population. The AIDI was developed using a 123-item food frequency questionnaire among 3503 women (56-74 years old) with high-sensitivity C-reactive protein (hsCRP) plasma concentration <20 mg/L. Using Spearman correlations, we identified 20 foods (AIDI-20) statistically significantly related to hsCRP. The median (range) of AIDI-20 was 8 (0-17) scores, and the median concentration of hsCRP in the lowest versus the highest quintile of AIDI-20 (≤6 vs. ≥11 scores) varied by 80% (1.8 vs. 1.0 mg/L, respectively). In a multivariable-adjusted linear regression model, women in the highest quintile of AIDI-20 compared with those in the lowest had a 26% (95% confidence interval [CI] 18-33%; p-trend <0.001) lower hsCRP concentration; each 1-score increment in the AIDI-20 was associated with a 0.06 (95% CI 0.04-0.08) mg/L lower hsCRP. The observed association between the AIDI-20 and hsCRP was robust by all hsCRP levels and in subgroups defined by inflammatory-related factors. Our results lead to the hypothesis that the empirically developed questionnaire-based dietary anti-inflammatory index may predict low-grade systemic inflammation. Antioxid. Redox Signal. 28, 78-84.

Keywords
C-reactive protein, anti-inflammatory index, diet, food, inflammation
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-337200 (URN)10.1089/ars.2017.7330 (DOI)000415967200006 ()28877589 (PubMedID)
Funder
Forte, Swedish Research Council for Health, Working Life and Welfare, 2015-00778Swedish Research Council, 2015-05997Swedish Research Council Formas, FR 2016/0004
Available from: 2017-12-21 Created: 2017-12-21 Last updated: 2018-01-17Bibliographically approved
Michaëlsson, K., Melhus, H. & Larsson, S. C. (2018). Serum 25-Hydroxyvitamin D Concentrations and Major Depression: A Mendelian Randomization Study. Nutrients, 10(12), Article ID 1987.
Open this publication in new window or tab >>Serum 25-Hydroxyvitamin D Concentrations and Major Depression: A Mendelian Randomization Study
2018 (English)In: Nutrients, ISSN 2072-6643, E-ISSN 2072-6643, Vol. 10, no 12, article id 1987Article in journal (Refereed) Published
Abstract [en]

Whether vitamin D insufficiency is a contributing cause of depression remains unclear. We assessed whether serum 25-hydroxyvitamin D (S-25OHD) concentrations, the clinical marker of vitamin D status, were associated with major depression using Mendelian randomization. We used summary statistics data for six single-nucleotide polymorphisms significantly associated with S-25OHD concentrations in the Study of Underlying Genetic Determinants of Vitamin D and Highly Related Traits (SUNLIGHT) consortium and the corresponding data for major depression (n = 59,851 cases and 113,154 controls) from the Psychiatric Genomics Consortium. Genetically predicted S-25OHD concentrations were not associated with major depression. The odds ratio per genetically predicted one standard deviation decrease in S-25OHD concentrations was 1.02 (95% confidence interval 0.97-1.08; p = 0.44). The results of this study indicate that genetically lowered S-25OHD concentrations are not associated with increased risk of developing major depression.

Place, publisher, year, edition, pages
MDPI, 2018
Keywords
depression, Mendelian randomization, single nucleotide polymorphisms, vitamin D
National Category
Nutrition and Dietetics
Identifiers
urn:nbn:se:uu:diva-375576 (URN)10.3390/nu10121987 (DOI)000455073200168 ()30558284 (PubMedID)
Funder
Swedish Research Council
Available from: 2019-02-01 Created: 2019-02-01 Last updated: 2019-02-01Bibliographically approved
Lind, T., Lind, P. M., Hu, L. & Melhus, H. (2018). Studies of indirect and direct effects of hypervitaminosis A on rat bone by comparing free access to food and pair-feeding.. Upsala Journal of Medical Sciences, 123(2), 82-85
Open this publication in new window or tab >>Studies of indirect and direct effects of hypervitaminosis A on rat bone by comparing free access to food and pair-feeding.
2018 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 123, no 2, p. 82-85Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The most prominent features of hypervitaminosis A in rats are spontaneous fractures and anorexia. Since caloric restriction induces alterations in bone, some effects could be secondary to loss of appetite. To clarify the mechanisms behind vitamin A-induced bone fragility it is necessary to distinguish between direct and indirect effects.

MATERIALS AND METHODS: In this study we compared rats fed high doses of vitamin A both with pair-fed controls, which were fed the same amount of chow as that consumed by the vitamin A group to keep food intake the same, and to controls with free access to food.

RESULTS: In contrast to the pair-fed animals, rats in the free access group fed high doses of vitamin A for 7 days had 13% lower food intake, 15% lower body weight, and 2.7% shorter femurs compared with controls. In addition, serum biomarkers of bone turnover were reduced. Peripheral quantitative computed tomography of the femurs showed that the bone mineral content, cross sectional area, and periosteal circumference were similarly reduced in the pair-fed and free access groups. However, bone mineral density (BMD) and cortical parameters were only significantly decreased in the free access group.

CONCLUSIONS: Our data indicate that the major direct short-term effect of high doses of vitamin A on rat bone is a reduced bone diameter, whereas the effects on bone length, serum biomarkers of bone turnover, BMD, and bone cortex appear to be mainly indirect, caused by a systemic toxicity with loss of appetite, reduced food intake, and general effects on growth.

Keywords
Bone, bone turnover serum biomarkers, pQCT, pair-fed, rat, vitamin A
National Category
Nutrition and Dietetics General Practice
Identifiers
urn:nbn:se:uu:diva-351381 (URN)10.1080/03009734.2018.1448020 (DOI)000438159000002 ()29697007 (PubMedID)
Available from: 2018-05-24 Created: 2018-05-24 Last updated: 2018-09-14Bibliographically approved
Mitchell, A., Fall, T., Melhus, H., Wolk, A., Michaëlsson, K. & Byberg, L. (2018). Type 2 Diabetes in Relation to Hip Bone Density, Area, and Bone Turnover in Swedish Men and Women: A Cross-Sectional Study. Calcified Tissue International, 103(5), 501-511
Open this publication in new window or tab >>Type 2 Diabetes in Relation to Hip Bone Density, Area, and Bone Turnover in Swedish Men and Women: A Cross-Sectional Study
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2018 (English)In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 103, no 5, p. 501-511Article in journal (Refereed) Published
Abstract [en]

Men and women with type 2 diabetes mellitus (T2DM) have higher risk of hip fracture, but the mechanisms are not fully understood. We aimed to investigate how T2DM, glucose, and insulin were associated with femoral bone mineral density (BMD), bone mineral area (BMA), and bone turnover markers. We used two cross-sectional cohorts: the Uppsala Longitudinal Study of Adult Men (ULSAM, n = 452, mean age 82 years) and the Swedish Mammography Cohort Clinical (SMCC, n = 4713, mean age 68 years). We identified men and women with normal fasting glucose (NFG), impaired fasting plasma glucose (IFG), and T2DM. BMD and BMA at the total hip and femoral shaft were measured using dual energy X-ray absorptiometry (DXA). Bone turnover markers; CrossLaps and osteocalcin were measured in women. Linear regression models were applied. Men and women showed a progressively higher BMD following the clinical cutoffs of fasting glucose from NFG to IFG to T2DM. In contrast, there was a progressively lower BMA. Men and women with T2DM, compared to those with NFG, had lower BMA at the total hip (- 1.7%; 95% CI - 3.2, - 0.2 and - 1.0%; 95% CI - 1.6, - 0.4) and the femoral shaft (- 2.0%; 95% CI - 3.5, - 0.4 and - 0.6%; 95% CI - 1.2, - 0.01), respectively. T2DM was associated with lower concentrations of CrossLaps (- 8.1%; 95% CI - 12.7, - 3.6) and osteocalcin (- 15.2%; 95% CI - 19.0, - 11.2). These cross-sectional results indicate that those with T2DM have smaller bone area and lower bone turnover, which could increase the risk of hip fracture.

Keywords
Bone mineral area, Bone turnover markers, Glucose, Insulin, Type 2 diabetes mellitus
National Category
Public Health, Global Health, Social Medicine and Epidemiology Orthopaedics
Identifiers
urn:nbn:se:uu:diva-366085 (URN)10.1007/s00223-018-0446-9 (DOI)000447965400005 ()29946974 (PubMedID)
Available from: 2018-11-16 Created: 2018-11-16 Last updated: 2019-01-08Bibliographically approved
Lind, T., Öhman, C., Calounova, G., Rasmusson, A., Andersson, G., Pejler, G. & Melhus, H. (2017). Excessive dietary intake of vitamin A reduces skull bone thickness in mice. PLoS ONE, 12(4), Article ID e0176217.
Open this publication in new window or tab >>Excessive dietary intake of vitamin A reduces skull bone thickness in mice
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2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 4, article id e0176217Article in journal (Refereed) Published
Abstract [en]

Calvarial thinning and skull bone defects have been reported in infants with hypervitaminosis A. These findings have also been described in humans, mice and zebrafish with loss-of-function mutations in the enzyme CYP26B1 that degrades retinoic acid (RA), the active metabolite of vitamin A, indicating that these effects are indeed caused by too high levels of vitamin A and that evolutionary conserved mechanisms are involved. To explore these mechanisms, we have fed young mice excessive doses of vitamin A for one week and then analyzed the skull bones using micro computed tomography, histomorphometry, histology and immunohistochemistry. In addition, we have examined the effect of RA on gene expression in osteoblasts in vitro. Compared to a standard diet, a high dietary intake of vitamin A resulted in a rapid and significant reduction in calvarial bone density and suture diastasis. The bone formation rate was almost halved. There was also increased staining of tartrate resistant acid phosphatase in osteocytes and an increased perilacunar matrix area, indicating osteocytic osteolysis. Consistent with this, RA induced genes associated with bone degradation in osteoblasts in vitro. Moreover, and in contrast to other known bone resorption stimulators, vitamin A induced osteoclastic bone resorption on the endocranial surfaces.

National Category
Clinical Medicine Engineering and Technology
Identifiers
urn:nbn:se:uu:diva-322801 (URN)10.1371/journal.pone.0176217 (DOI)000399875900119 ()28426756 (PubMedID)
Available from: 2017-09-12 Created: 2017-09-12 Last updated: 2017-11-29Bibliographically approved
Zillikens, M. C., Demissie, S., Hsu, Y.-H., Yerges-Armstrong, L. M., Chou, W.-C., Stolk, L., . . . Kiel, D. P. (2017). Large meta-analysis of genome-wide association studies identifies five loci for lean body mass. Nature Communications, 8, Article ID 80.
Open this publication in new window or tab >>Large meta-analysis of genome-wide association studies identifies five loci for lean body mass
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2017 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 80Article in journal (Refereed) Published
Abstract [en]

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 x 10(-8)) or suggestively genome wide (p < 2.3 x 10(-6)). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/ near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/ near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2017
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-332854 (URN)10.1038/s41467-017-00031-7 (DOI)000405818900003 ()28724990 (PubMedID)
Funder
Swedish Research CouncilSwedish Foundation for Strategic Research Torsten Söderbergs stiftelseRagnar Söderbergs stiftelse
Available from: 2017-11-08 Created: 2017-11-08 Last updated: 2018-08-24Bibliographically approved
Warensjö Lemming, E., Byberg, L., Melhus, H., Wolk, A. & Michaëlsson, K. (2017). Long-term a posteriori dietary patterns and risk of hip fractures in a cohort of women. European Journal of Epidemiology, 32(7), 605-616
Open this publication in new window or tab >>Long-term a posteriori dietary patterns and risk of hip fractures in a cohort of women
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2017 (English)In: European Journal of Epidemiology, ISSN 0393-2990, E-ISSN 1573-7284, Vol. 32, no 7, p. 605-616Article in journal (Refereed) Published
Abstract [en]

Dietary pattern analysis is a useful tool to study the importance of food components in the context of a diet and how they relate to health and disease. The association between dietary patterns and fractures is at present uncertain. We aimed to study associations between dietary patterns and risk of hip fracture in the Swedish Mammography Cohort, including 56,736 women (median baseline age 52 years). Diet data was collected in food frequency questionnaires at two investigations and dietary patterns were defined by principal component analysis using 31 food groups. Information on hip fractures was collected from the Swedish National Patient Register. Multivariable adjusted hazard ratios (HR) with 95% confidence intervals (CI) were estimated in Cox proportional hazards regression analysis. The two patterns identified-the healthy and Western/convenience dietary patterns-were time-updated and analysed. During a median follow-up time of 25.5 years, 4997 women experienced a hip fracture. Hip fracture rate was 31% lower in the highest compared to the lowest quartile of the healthy dietary pattern [HR (95% CI) 0.69 (0.64; 0.75)]. In contrast, women in the highest compared to the lowest quartile of the Western/convenience dietary pattern had a 50% higher [HR (95% CI) 1.50 (1.38; 1.62)] hip fracture rate. Further, in each stratum of a Western/convenience dietary pattern a higher adherence to a healthy dietary pattern was associated with less hip fractures. The present results suggest that a varied healthy diet may be beneficial for the prevention of fragility fractures in women.

Keywords
Dietary pattern, Healthy dietary pattern, Western dietary pattern, Principal component analysis, Hip fractures, Food frequency questionnaire
National Category
Orthopaedics Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:uu:diva-334099 (URN)10.1007/s10654-017-0267-6 (DOI)000408307500008 ()
Available from: 2017-11-21 Created: 2017-11-21 Last updated: 2018-08-24Bibliographically approved
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