Kristin Holvik

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Aim: We aimed to study the association between α-tocopherol concentrations in serum and risk of hip fractures in older men and women. Methods: In the Norwegian Epidemiologic Osteoporosis Studies (NOREPOS) we performed a case-cohort analysis in 21,774 men and women aged 65-79 years (mean 72 y) who underwent baseline examinations in four community-based health studies during 1994-2001. Data on incident hip fractures were retrieved from electronic patient administrative systems. Frozen serum samples from baseline were analyzed in participants who suffered a hip fracture during median 8.2 years of follow-up (n=1168) and in sex-stratified random samples from baseline (n=1434). α-tocopherol was determined by high pressure liquid chromatography (HPLC)-fluorescence detection. Cox proportional hazards regression adapted for the case-cohort design was performed with adjustment for age, sex, and study center. Results: We observed a linear inverse relation between serum α-tocopherol levels and hip fracture, with hazard ratio (HR) 1.11 (95% CI 1.04-1.20) per 10 µmol/l lower serum α-tocopherol. HR of hip fracture in the lowest (<22.6 µmol/l) compared with the highest (>=38.3 µmol/l) quartile of serum α-tocopherol was 1.51 (95% CI 1.17-1.95). Adjustment for serum concentrations of 25(OH)D and retinol, smoking, month of blood sample, body mass index, education, physical inactivity and self-rated health yielded similar results. Conclusion: Low serum concentrations of α-tocopherol were associated with increased risk of hip fracture in older Norwegian men and women.

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The increased oxidative stress associated with ageing influences the formation and survival of bone forming and bone resorbing cells. Vitamin E, of which α-tocopherol is the most abundant form in human tissues, is a plant-derived lipid soluble substance with potent antioxidant properties. The relation between vitamin E concentrations in blood and risk of hip fracture has not previously been investigated in a population-based study. We aimed to study the association between α-tocopherol levels in serum and risk of hip fractures in elderly men and women in Norway, the population with the world’s highest hip fracture incidence. In the Norwegian Epidemiologic Osteoporosis Studies (NOREPOS), we performed a case-cohort analysis in 21,774 men and women aged 65-79 years (mean 72 y) who underwent baseline examinations in four population-based health studies during 1994-2001. Data on incident hip fractures occurring up to 10.7 years of follow-up were retrieved from electronic patient administrative systems. Frozen serum samples from baseline were analyzed in participants who suffered a hip fracture during follow-up (n=1179; 307 men and 872 women) and in sex-stratified random samples from baseline (n=1447, including 89 of those who later suffered a hip fracture). α-tocopherol in serum was determined by high pressure liquid chromatography (HPLC)-fluorescence detection. Cox proportional hazards regression adapted for the case-cohort design was performed with adjustment for age, sex, and study center. Median (25, 75-percentile) serum α-tocopherol concentration was 30.0 (22.6, 38.3) µmol/l. A linear inverse relation between serum α-tocopherol levels and hip fracture was observed, with hazard ratio (HR) 1.12 (95% CI 1.04-1.20) per 10 µmol/l lower serum α-tocopherol. HR of hip fracture in the lowest (<22.6 µmol/l) compared with the highest (>=38.3 µmol/l) quartile of serum α-tocopherol was 1.53 (95% CI 1.18-1.97). The trend was linear across quartiles (p<0.001). Additional adjustment for body mass index, cigarette smoking, month of blood draw, and length of education yielded similar results. In conclusion, low serum concentrations of α-tocopherol were associated with increased risk of hip fracture in both men and women.

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Background: Norwegians have among the highest hip fracture rates worldwide. Vitamin D status is generally good and vitamin A intake is relatively high in Norway. Increased fracture risk at high intakes and serum levels of retinol have been observed in earlier epidemiologic studies. Objective: To study whether serum concentration of vitamins D and A in elderly Norwegians are related to risk of hip fracture, and whether high serum vitamin A (retinol) may counteract a possible protective effect of vitamin D. Methods: N=21,774 men and women aged 65-79 attended four community-based health studies during 1994- 2001. Subsequent hip fractures were retrieved from hospitals’ patient administrative systems, with maximum follow-up 10.7 years. 25(OH)D was determined by HPLC-APCI-MS and retinol by HPLC-UV in baseline serum samples in cases and weighted random samples of men and women. Adjusted Cox proportional hazards regression modified for the case-cohort design was performed using R. Results: During median follow-up 8.2 years, 340 men (3.4%) and 892 women (7.5%) suffered a hip fracture. We found an inverse association between 25(OH)D and hip fracture; HR 1.35 (95% CI 1.07-1.70) for <50 nmol/l compared with >75 nmol/l. Compared with middle retinol levels (2-3 μmol/l), low levels (<2 μmol/l) was associated with increased hip fracture risk: HR 1.27 (95% CI 1.00-1.62). In stratified analyses, the inverse association between 25(OH)D and risk of hip fracture was apparent at low retinol levels in men, but only at high retinol levels in women. Conclusion: Both 25(OH)D and retinol were inversely associated with risk of hip fracture.

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Objective: The relationship between vitamin D status and risk of hip fracture has not been established. Our aim was to study this relationship in a population-based case-cohort study of elderly men and women in Norway. Methods: N=21,774 men and women aged 65-79 years attended baseline examinations in four population-based health studies in Norway during 1994-2001. Subsequent hip fractures were retrieved from patient administrative systems and verified by X-ray or medical records, with maximum follow-up 10.7 years. All hip fracture cases and randomly sampled gender-specific subcohorts of men (4.5% yielding n=444) and women (9.0% yielding n=1058) were selected for analysis of 25-hydroxyvitamin D (25(OH)D) in serum samples from baseline stored at −80°C. 25(OH)D2 and 25(OH)D3 was determined by HPLC-APCI-MS. We performed Cox proportional hazards regression of hip fracture vs. quartiles of total 25(OH)D, with left-truncation for age at baseline and right-censoring for age at exit, inverse probability weighting and robust variance, adjusted for study site. Additional analyses were adjusted for season of blood sample, body mass index, daily cigarette smoking, and self-rated health. Results: During a median follow-up of 8.2 years, 1232 individuals (340 men (3.4%) and 892 women (7.5%)) sustained a hip fracture. The subcohorts included 1502 individuals of whom 93 were also cases. Intact frozen serum was available and successfully analysed in n=2526 (95.6%). In men, there was a trend of increasing risk of hip fracture with decreasing 25(OH)D, statistically significant for Q1 (<43.3 nmol/l) vs. Q4 (>=69.2 nmol/l): HR 1.68 (95% CI 1.05-2.68) in the main analysis, and HR 1.65 (95% CI 1.01-2.67) in the fully adjusted analysis. In women, there was no significant relation between 25(OH)D and hip fracture. However, there was a tendency of increased HR in decreasing quartiles of 25(OH)D in adjusted analysis, with HR 1.19 (95% CI 0.90-1.59) in Q1 (<41.5 nmol/l) vs. Q4 (>=67.0 nmol/l). Conclusion: According to these preliminary analyses, lower vitamin D status was significantly associated with increased HR of hip fracture in men, but not women.

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Background: A positive association between serum 25-hydroxyvitamin D (s-25(OH)D) levels and BMD is commonly seen in observational studies. It has been suggested that a positive effect of vitamin D on BMD may be counteracted by high concentrations of retinol. Methods: In a sample of elderly men and women born 1924-27 who participated in two population-based osteoporosis health studies in Bergen (59°N) and Oslo (60°N), and who were randomly selected to the subcohort of a case-cohort study, 170 participants (72 men and 98 women) had BMD measurements performed by DXA in 1998-2001 (age at examination 71-77 years). DXA measurements of total femur were performed on two different densitometers (Lunar Expert and Lunar DPX-L) that were cross-calibrated for this purpose. Serum analyses of 25-hydroxyvitamin D and retinol were performed by respectively HPLC-APCI-MS and HPLC-UV, simultaneously in the same laboratory. Linear regression analyses were stratified by gender. Age, body mass index, and season of blood sampling were included as covariates. Results: Mean (SD) total femur BMD was 0.94 (0.15) g/cm2 in men and 0.81 (0.11) g/cm2 in women (p<0.001). Mean (SD) s-25(OH)D and s-retinol was 58.1 (23.1) nmol/l and 2.49 (0.73) µmol/l, respectively, and not significantly different in women than men. The association between s-25(OH)D and BMD was not significant. The interaction term between s-retinol and s-25(OH)D on BMD was statistically significant for men (p=0.016) but not women (p=0.23). In men, the coefficient for ΔBMD per 20 nmol/l increase in s-25(OH)D was reduced by 0.036 g/cm2 (corresponding to 1/4 SD) for each µmol/l higher s-retinol. Conclusion: The notion that a positive association between vitamin D status and BMD may be dependent on serum retinol levels was supported by these preliminary data in men, but not women.

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Background: Pakistanis and ethnic Norwegians living in Oslo have similar bone mineral density, in spite of a much lower vitamin D status in the Pakistanis. Although ethnic Norwegians have a high fracture rate and low bone mineral density, they are known to have a relatively high calcium intake. Milk and cheese constitute 70% of the calcium intake in the average Norwegian diet. Objective: To explore calcium intake from dairy products and its relation to calcium economy expressed by serum levels of parathyroid hormone in Pakistanis and ethnic Norwegians living in Oslo. Methods: The data was collected as part of the large cross-sectional Oslo Health Study 2000-2001. All participants filled in questionnaires concerning diet and lifestyle, and a subsample had their serum analyzed with respect to vitamin D metabolites and intact parathyroid hormone (iPTH). We estimated daily calcium intake from milk and cheese, based on four questions about usual intake. For the current analysis, our sample consisted of 71 Pakistani men and 51 Pakistani women of ages 30-60 years, and 254 Norwegian men and 218 Norwegian women of ages 45-60 years. Results: iPTH was significantly higher in Pakistanis than in Norwegians (age adjusted mean 6.6 pmol/l in Pakistanis vs. 5.1 pmol/l in Norwegians, p<0.0005). Estimated calcium intake from milk and cheese was lower in Pakistanis than in Norwegians, but not significantly so (mean 296 mg in Pakistani men, 249 mg in Pakistani women, 348 mg in Norwegian men and 313 mg in Norwegian women). Linear regression and Pearson correlations showed a negative relationship between estimated calcium intake and iPTH that was significant in Norwegian women (-0.2 pmol/l per 100 mg, r=-0.20, p=0.004) and Pakistani men (-0.3 pmol/l per 100 mg, r=-0.27, p=0.021), but not in Norwegian men (p=0.41) or Pakistani women (p=0.41). This was unaltered when controlling for age and serum 25-hydroxyvitamin D levels. Conclusion: We found that estimated daily calcium intake from milk and cheese, based on four simple questions in the Oslo Health Study questionnaire, was a significant negative predictor of parathyroid hormone levels in Norwegian women and Pakistani men, but not in Norwegian men or Pakistani women.

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Many types of vitamin supplements are available on the market, but little is known about whether vitamin D3 obtained from fat-containing capsules differs in bioavailability from that of solid tablets. We performed a randomized trial in order to compare two common vitamin D supplements. Our objective was to test whether four weeks of daily supplementation with 10 µg vitamin D3 given as a fish oil capsule produces a larger increase in serum 25-hydroxyvitamin D levels compared with the same dose of vitamin D3 given as a multivitamin tablet. A total of 55 healthy subjects aged 19-48 yr (mean 28.5 yr) completed the study during late winter 2005. After completing a self-administered questionnaire about diet and sun exposure and having a non-fasting venous blood sample drawn, participants were randomized to receive either multivitamin tablets of type Vitaplex ABCD, or fish oil capsules. A second blood sample was drawn after 28 days of supplementation. The vitamin D3 content of both supplements was assessed by an independent laboratory; mean (SD) 9.79 (1.51) µg and 9.99 (0.23) µg, respectively. Statistical analysis was performed using linear regression analysis with change in serum 25-hydroxyvitamin D as the dependent variable and intervention supplement as the independent variable, adjusted for serum 25-hydroxyvitamin D at baseline. In the total sample, mean (95% CI) serum 25-hydroxyvitamin D was 44.3 (38.0, 50.7) nmol/l at baseline, and it increased by 34.1 (30.5, 37.6) nmol/l during the intervention. The increase in serum 25-hydroxyvitamin D was not significantly different between the two groups (p=0.33). We conclude that fish oil capsules and multivitamin tablets containing 10 µg vitamin D3 produced a similar increase in serum 25-hydroxyvitamin D levels over a 4-week period.

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We have shown that the prevalence of secondary hyperparathyroidism (i.e. low serum 25-hydroxy vitamin D and elevated parathyroid hormone levels) was much higher in Pakistan-born than in Norwegian-born persons attending the Oslo Health Study. In spite of this, bone density in the Pakistanis was at least as high as that in Norwegians. We wanted to explore possible ethnic differences in bone turnover in these groups. The aim was to study the levels of biochemical markers of bone turnover and the correlation between parathyroid hormone levels and bone marker levels in Pakistanis and Norwegians in Oslo. Serum levels of intact parathyroid hormone (s-iPTH), osteoblast markers osteocalcin (s-OC) and bone specific alkaline phosphatase (s-bALP), and osteoclast marker tartrate resistant acid phosphatase (s-TRAP) were measured in a subgroup of Pakistanis and Norwegians participating in the large population-based Oslo Health Study 2000-2001. We here present results for 141 Pakistani men and women aged 30-45 years, and 167 Norwegian men and women aged 45 years. Mean age-adjusted s-OC was 1.23 nmol/l in Pakistanis and 1.45 nmol/l in Norwegians (p=0.006), a difference corresponding to nearly 1/2 SD. Norwegian women had s-OC levels 0.32 nmol/l higher than Pakistani women (p=0.010), whereas Norwegian men had s-OC levels 0.15 nmol/l higher than Pakistani men (ns). Mean age-adjusted s-bALP was 19.1 U/l in Pakistanis and 17.6 U/l in Norwegians (ns). Mean age-adjusted s-TRAP was 2.30 U/l in Pakistanis and 2.43 U/l in Norwegians (ns). In Norwegian women there was a positive correlation between s-iPTH and s-bALP (r=0.30, p=0.004), and between s-iPTH and s-OC (r=0.25, p=0.017). In Pakistani women there was a positive correlation between s-iPTH and s-bALP (r=0.29, p=0.020), and a tendency to a positive correlation between s-iPTH and s-OC (r=0.23, p=0.065). S-iPTH was not correlated to s-TRAP in any group. There was no correlation between s-iPTH and bone marker levels in men. In conclusion, there were no striking ethnic differences in bone turnover markers, although levels tended to be higher in Norwegians. Although bone marker levels were correlated to parathyroid hormone levels also in Pakistani women, the widespread secondary hyperparathyroidism in Pakistanis does not seem to influence bone turnover adversely at this age.

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Background We have shown that Pakistan-born persons had a much higher frequency of serious vitamin D deficiency compared to Norwegian-born persons participating in the Oslo Health Study 2000-2001. This is a well-known risk factor for metabolic bone disease. In spite of this, bone density in Pakistanis was at least as high as that in Norwegians. Aim To explore if there are ethnic differences in bone turnover, expressed by serum levels of biochemical markers of bone turnover in Pakistanis and Norwegians living in Oslo. Methods Serum levels of bone formation markers osteocalcin (s-OC) and bone specific alkaline phosphatase (s-bALP) as well as bone resorption marker tartrate resistant acid phosphatase (s-TRAP) were measured in a subgroup of Pakistani and Norwegian men and women participating in the large population-based Oslo Health Study 2000-2001. We here present results for 141 Pakistani men and women aged 30, 40, and 45, and 167 Norwegian men and women aged 45. Results Mean age-adjusted s-OC was 1.23 nmol/l in Pakistanis and 1.45 nmol/l in Norwegians (p=0.006). Norwegian women had s-OC levels 0.32 nmol/l higher than Pakistani women (p=0.010), and Norwegian men had s-OC levels 0.15 nmol/l higher than Pakistani men (ns). Mean age-adjusted s-bALP was 19.1 U/l in Pakistanis and 17.6 U/l in Norwegians (ns). Mean age-adjusted s-TRAP was 2.30 U/l in Pakistanis and 2.43 U/l in Norwegians (ns). We will further investigate the relationship between bone marker levels and bone mineral density in the sample. Conclusions Bone turnover seems to be slightly higher in young adult Norwegians compared to Pakistanis, although there are no striking ethnic differences. The widespread vitamin D deficiency in Pakistanis does not seem to influence bone turnover adversely in the age groups studied.