Ragnar Martin Joakimsen

Low serum 25-hydroxyvitamin D levels are associated with increased all-cause mortality risk in a general population: the Tromsø study.

OBJECTIVE Ecologic and observational studies have suggested an association between serum 25-hydroxyvitamin D (25(OH)D) levels and cardiovascular disease (CVD) risk factors, CVD mortality, and cancer mortality. Based on this, low serum 25(OH)D levels should be associated with higher all-cause mortality in a general population. This hypothesis was tested in the present study. DESIGN The Tromsø study is a longitudinal population-based multipurpose study initiated in 1974 with focus on lifestyle-related diseases. Our data are based on the fourth Tromsø study carried out in 1994-1995. METHODS Information about death and cause of death was registered by obtaining information from the National Directory of Residents and the Death Cause Registry. Serum 25(OH)D was measured in 7161 participants in the fourth Tromsø study. Results are presented for smokers (n=2410) and non-smokers (n=4751) separately as our immunoassay seems to overestimate 25(OH)D levels for smokers. RESULTS During a mean 11.7 years of follow-up, 1359 (19.0%) participants died. In multivariate regression models, there was a significantly increased risk of all-cause mortality (hazard ratio (HR) 1.32, confidence interval (CI) 1.07-1.62) among non-smoking participants in the lowest 25(OH)D quartile when compared with participants in the highest quartile. Equivalent results for smokers were not significant (HR 1.06, CI 0.83-1.35). CONCLUSIONS Low serum 25(OH)D levels were associated with increased all-cause mortality for non-smokers, but the results did not reach statistical significance for smokers. However, low 25(OH)D levels are known to be associated with impaired general health, and randomized controlled studies are needed to address the question of causality.

Physical activity and predisposition for hip fractures : A review

Studies on the association between physical activity and hip fractures are reviewed. All the studies, which comprise four follow-up studies, one nested case-control study and 17 case-control studies, suggest a protective effect of physical activity with regard to hip fractures. The association is strong and consistent with physical activity in leisure, weaker with respect to physical activity at work. The association is present for physical activity from childhood to adult age, and it is consistent in study populations from the USA, Australia, Asia and Northern and Southern Europe, in spite of very different hip fractures incidences in these populations. The magnitude of the association is difficult to assess because of varying criteria for exposure, but to be among the physically active seems to reduce the risk of later hip fracture by up to 50%. It seems that even daily chores, such as climbing stairs and walking, protect against hip fracture.

The Tromsø Study: Physical Activity and the Incidence of Fractures in a Middle-Aged Population

We have studied the relation of occupational and recreational physical activity to fractures at different locations. All men born between 1925 and 1959 and all women born between 1930 and 1959 in the city of Tromsø were invited to participate in surveys in 1979–1980 and 1986–1987 (The Tromsø Study). Of 16,676 invited persons, 12,270 (73.6%) attended both surveys. All nonvertebral fractures (n = 1435) sustained from 1988 to 1995 were registered in the only hospital in the area. Average age in the middle of the follow‐up period (December 31, 1991) was 47.3 years among men and 45.1 years among women, ranging from 32 to 66 years. Fracture incidence increased with age at all locations among women, but it decreased with or was independent of age among men. Low‐energetic fractures constituted 74.4% of all fractures among women and 55.2% among men. When stratifying by fracture location, the most physically active persons among those 45 years or older suffered fewer fractures in the weight‐bearing skeleton (relative risk [RR] 0.6, confidence interval [CI] 0.4–0.9, age‐adjusted), but not in the non–weight‐bearing skeleton (RR 1.0, CI 0.7–1.2, age‐adjusted) compared with sedentary persons. The relative risk of a low‐energetic fracture in the weight‐bearing skeleton among the most physically active middle‐aged was 0.3 (CI 0.1–0.7) among men and 0.9 (CI 0.4–1.8) among women compared with the sedentary when adjusted for age, body mass index, body height, tobacco smoking, and alcohol and milk consumption. It seems that the beneficial effect on the skeleton of weight‐bearing activity is reflected also in the incidence of fractures at different sites.

Baseline serum 25‐hydroxyvitamin D concentrations in the Tromsø Study 1994–95 and risk of developing type 2 diabetes mellitus during 11 years of follow‐up

Diabet. Med. 27, 1107–1115 (2010)

The Relationship between Serum TSH and Bone Mineral Density in Men and Postmenopausal Women: The Tromsø Study

BACKGROUND Hyperthyroidism is associated with osteoporosis, and it has recently been suggested that thyroid-stimulating hormone (TSH) has bone protective properties. We wanted to explore the relationship between serum TSH and bone mineral density (BMD) in a healthy population. METHODS This study included 993 postmenopausal females and 968 males with valid measurements of BMD at the hip and forearm in the fifth Tromsø study conducted in 2001. Participants with major diseases or medication affecting BMD or thyroid function were excluded. The subjects were divided into six different groups based on the 2.5 and 97.5 percentiles of serum TSH and the quartiles in between. Multiple linear regression adjusting for age; weight; height; smoking status; physical activity level; and for women, use of hormonal replacement therapy was used in the analyses. RESULTS After multivariate adjustment, the 28 men and 18 women with serum TSH below the 2.5 percentile had significantly lower BMD at the ultradistal (women) and distal (both sexes) forearm than the 921 men and 950 women with serum TSH in the normal range. Also, the 25 postmenopausal women with serum TSH above the 97.5 percentile had significantly higher BMD at the femoral neck than women with serum TSH in the normal range. Across the normal range of serum TSH, there was no association between TSH and BMD, and serum TSH as a continuous variable had no effect on BMD in the multiple linear regression model. CONCLUSIONS Within the normal range of serum TSH, serum TSH was not associated with BMD. The small groups of men and women with serum TSH consistent with hyperthyroidism had lower BMD at the forearm than those with serum TSH in the normal range.

Polymorphisms Related to the Serum 25-Hydroxyvitamin D Level and Risk of Myocardial Infarction, Diabetes, Cancer and Mortality. The Tromsø Study

Objective Low serum 25(OH)D levels are associated with cardiovascular risk factors, and also predict future myocardial infarction (MI), type 2 diabetes (T2DM), cancer and all-cause mortality. Recently several single nucleotide polymorphisms (SNPs) associated with serum 25-hydroxyvitamin D (25(OH)D) level have been identified. If these relations are causal one would expect a similar association between these SNPs and health. Methods DNA was prepared from subjects who participated in the fourth survey of the Tromsø Study in 1994–1995 and who were registered with the endpoints MI, T2DM, cancer or death as well as a randomly selected control group. The endpoint registers were complete up to 2007–2010. Genotyping was performed for 17 SNPs related to the serum 25(OH)D level. Results A total of 9528 subjects were selected for genetic analyses which were successfully performed for at least one SNP in 9471 subjects. Among these, 2025 were registered with MI, 1092 with T2DM, 2924 with cancer and 3828 had died. The mean differences in serum 25(OH)D levels between SNP genotypes with the lowest and highest serum 25(OH)D levels varied from 0.1 to 7.8 nmol/L. A genotype score based on weighted risk alleles regarding low serum 25(OH)D levels was established. There was no consistent association between the genotype score or individuals SNPs and MI, T2DM, cancer, mortality or risk factors for disease. However, for rs6013897 genotypes (located at the 24-hydroxylase gene (CYP24A1)) there was a significant association with breast cancer (P<0.05). Conclusion Our results do not support nor exclude a causal relationship between serum 25(OH)D levels and MI, T2DM, cancer or mortality, and our observation on breast cancer needs confirmation. Further genetic studies are warranted, particularly in populations with vitamin D deficiency. Trial Registration ClinicalTrials.gov NCT01395303

Features of the metabolic syndrome and the risk of non-vertebral fractures : The Tromso Study

Owing to a technical error, a number of non-vertebral fractures had not been included in the database. Owing to changes in the informed consents for some of the participants, at the time of repeated analyses, the study cohort changed from 27,159 to 26,905 participants. A total of 1,882 non-vertebral fractures (not 1,249 as stated in the publication) were registered. After excluding all subjects with missed measurements of any metabolic syndrome criteria (n=152), 750 men and 1108 women (not 438 men and 789 women as stated in the publication) suffered non-vertebral fractures. The risk estimates of the associations between having three or more of the metabolic syndrome criteria and nonvertebral fractures and changed to (RR 0.81, 95% CI 0.64– 1.04) in men and (RR 0.78, 95% CI 0.65–0.93) in women. The trend towards reduced fracture risk by increasing mean BP in men was no longer significant (Fig. 2). We apologize for any inconvenience caused by this unfortunate error. Osteoporos Int (2009) 20:839 DOI 10.1007/s00198-009-0847-8

What do Norwegian women and men know about osteoporosis

A survey of a random sample of 1514 Norwegian women and men aged 16–79 years was undertaken to investigate knowledge of osteoporosis and attitudes towards methods for preventing this disease. The interviews were carried out by Central Bureau of Statistics of Norway as part of their monthly national poll using a structured questionnaire. Women knew more about osteoporosis than did men (p<01). In both men and women increased knowledge of osteoporosis was correlated to a high level of education. Furthermore it was clearly demonstrated that knowing someone with osteoporosis or suffering from it oneself increased the knowledge of osteoporosis significantly in both women and men. Multiple regression analysis confirmed the univariate analyses, and education was the strongest predictive factor for knowledge. To a hypothetical question as many as two-thirds of the women answered that they would use long-term hormone replacement therapy (HRT) to prevent osteoporosis on the recommendation of their general practitioner. Their attitudes towards the use of estrogen therapy did not show any significant relation to age, but their reluctance towards HRT increased with education (p<001). When asked a question about their preferences regarding the use of physical activity as a means to prevent osteoporosis, older women preferred walking (p<.001), whereas younger women wanted more organized athletic activity (p<001). The data demonstrated that there was a high degree of general knowledge of osteoporosis and its consequences in the general population.

The Tromsø Study: Body Height, Body Mass Index and Fractures

Abstract: Tall persons suffer more hip fractures than shorter persons, and high body mass index is associated with fewer hip and forearm fractures. We have studied the association between body height, body mass index and all non-vertebral fractures in a large, prospective, population-based study. The middle-aged population of Tromsø, Norway, was invited to surveys in 1979/80, 1986/87 and 1994/95 (The Tromsø Study). Of 16 676 invited to the first two surveys, 12 270 attended both times (74%). Height and weight were measured without shoes at the surveys, and all non-vertebral fractures in the period 1988–1995 were registered (922 persons with fractures) and verified by radiography. The risk of a low-energy fracture was found to be positively associated with increasing body height and with decreasing body mass index. Furthermore, men who had gained weight had a lower risk of hip fractures, and women who had gained weight had a lower risk of fractures in the lower extremities. High body height is thus a risk factor for fractures, and 1 in 4 low-energy fractures among women today might be ascribed to the increase in average stature since the turn of the century. Low body mass index is associated with a higher risk of fractures, but the association is probably too weak to have any clinical relevance in this age category.

The serum 25-hydroxyvitamin D response to vitamin D supplementation is related to genetic factors, BMI, and baseline levels

OBJECTIVE The serum 25-hydroxyvitamin D (25(OH)D) level is not only dependent on vitamin D intake and production in the skin but also dependent on genetic factors. Thus, in large genome-wide association studies, it has been shown that single nucleotide polymorphisms (SNPs) in the vitamin D binding protein (DBP), as well as in enzymes related to activation or degradation of vitamin D and its metabolites, are as important for the serum 25(OH)D level as the effect of season. How these SNPs affect the serum 25(OH)D response to vitamin D supplementation is uncertain. DESIGN AND METHODS Data were pooled from three randomized controlled trials where 40, 000 IU vitamin D/week was given for 6 months. Serum 25(OH)D was measured before and at the end of the intervention, and the subjects were genotyped for SNPs related to the serum 25(OH)D level. RESULTS Baseline 25(OH)D levels were significantly related to SNPs in the DBP and CYP2R1 genes. Those with SNPs associated with the lowest baseline 25(OH)D levels also had the smallest increase (delta) after supplementation. Those with the lowest baseline serum 25(OH)D (without regard to genotypes) had the highest increase (delta) after supplementation. Subjects with high BMI had lowest baseline 25(OH)D levels and also the smallest increase (delta) after supplementation. CONCLUSIONS The serum 25(OH)D response to supplementation depends on genes, baseline level, and BMI. However, whether this is clinically important or not depends on the therapeutic window of vitamin D, an issue that is still not settled.