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American Journal of Epidemiology Advance Access originally published online on August 22, 2007
American Journal of Epidemiology 2007 166(11):1327-1336; doi:10.1093/aje/kwm210
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American Journal of Epidemiology © The Author 2007. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

ORIGINAL CONTRIBUTIONS

Association between Plasma 25-Hydroxyvitamin D Levels and Fracture Risk

The EPIC-Oxford Study

Andrew W. Roddam1, Rachel Neale2, Paul Appleby1, Naomi E. Allen1, Sarah Tipper1 and Timothy J. Key1

1 Cancer Research UK Epidemiology Unit, University of Oxford, Oxford, United Kingdom
2 Queensland Institute of Medical Research, Brisbane, Australia

Correspondence to Dr. Andrew Roddam, Cancer Research UK Epidemiology Unit, University of Oxford, Richard Doll Building, Roosevelt Drive, Oxford OX3 7LF, United Kingdom (e-mail: andrew.roddam{at}ceu.ox.ac.uk).

Received for publication April 18, 2007. Accepted for publication June 15, 2007.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
The importance of vitamin D for bone health is well established, but few data exist on the relation between plasma levels of 25-hydroxyvitamin D and risk of fracture. The authors examined this association within the EPIC-Oxford (European Prospective Investigation into Cancer and Nutrition-Oxford cohort) study of men and women in the United Kingdom (1993–1999). Five years after recruitment, participants completed a follow-up questionnaire where fracture incidence was self-reported. Plasma 25-hydroxyvitamin D concentration was measured in 730 incident fracture cases and 1,445 matched controls. There was a clear association between plasma 25-hydroxyvitamin D concentration and month of blood draw, the highest values being during the summer months. Among women, there were significant relations between 25-hydroxyvitamin D levels and age, body mass index, marital status, use of hormone therapy, physical activity, diet group, dietary intake of vitamin D, and alcohol. Similar relations were seen among men, although often they were nonsignificant because of smaller numbers. There was no evidence of an association between plasma 25-hydroxyvitamin D and fracture risk for men or women; the relative risks associated with a doubling of plasma 25-hydroxyvitamin D were 1.15 (95% confidence interval: 0.82, 1.61) and 0.95 (95% confidence interval: 0.80, 1.13), respectively. These results were not affected by adjustment for potential confounders and were consistent across a number of subgroups.

calcifediol; cohort studies; fractures, bone; 25-hydroxyvitamin D 2; vitamin D

Abbreviations: CI, confidence interval; EPIC-Oxford, European Prospective Investigation into Cancer and Nutrition-Oxford cohort


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Bone fractures represent a significant burden of both illness and associated health-care cost, especially in an aging population. The importance of vitamin D for bone health is well established, with a clear relation between low levels of vitamin D and high rates of bone turnover/loss and consequently low bone mineral density (1). However, although ecologic studies suggest that fracture incidence rates are higher in countries with poor vitamin D status (2), there is very little prospective evidence directly linking vitamin D status with fracture risk, the outcome which is of public health importance. Recent randomized trials have suggested that vitamin D supplementation alone is not associated with a reduced risk of fracture, although there is evidence that vitamin D supplements of 700–800 IU/day are associated with a reduced risk of hip and nonvertebral fracture (3, 4). Recent data from the Women's Health Initiative clinical trial showed that a daily supplement of 10 µg of vitamin D plus 1,000 mg of elemental calcium did not reduce fracture rates in postmenopausal women, although hip fracture risk was significantly lower in the treatment group when data were censored at the point when the women ceased to adhere to the study medication (5).

In this nested case-control study, we investigated the association between plasma 25-hydroxyvitamin D concentration and fracture risk among more than 2,000 free-living adults in the United Kingdom.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Participants
The European Prospective Investigation into Cancer and Nutrition-Oxford cohort (EPIC-Oxford) study was established partly by postal methods aimed at recruiting participants throughout the United Kingdom with a wide range of diets, including vegetarians and vegans, and partly through general practice surgeries in Oxfordshire, Buckinghamshire, and Greater Manchester; this study has been described in detail elsewhere (6). Participants (n = 65,469) completed a diet and lifestyle questionnaire and were also asked to provide a 30-ml blood sample. Blood samples were collected throughout the United Kingdom and transported to a laboratory in Norfolk by mail at ambient temperature. Blood fractions (serum, plasma, red cells, and buffy coat for DNA extraction) were aliquoted into 0.5-ml straws, which were then heat sealed at both ends and stored in liquid nitrogen tanks at –196°C.

The EPIC-Oxford study was approved by the Multicentre Research Ethics Committee for Scotland, and all participants gave informed consent.

Nutrient intake
The recruitment questionnaire included a food frequency questionnaire that asked participants to estimate their average frequency of intake of each of 130 foods over the previous 12 months (7). Answers to these questions were used to estimate participants' daily nutrient intake by standard portion sizes, derived largely from the former Ministry of Agriculture, Fisheries, and Food (8) and the fifth edition of McCance & Widdowson's The Composition of Foods (9) and its supplements. Estimated nutrient intakes used in this analysis were energy, calcium, and vitamin D. Estimated nutrient intakes were deemed to be reliable if less than 20 percent of relevant food frequency codes were missing and if estimated daily energy intakes were not less than 800 kcal or more than 4,000 kcal for men and not less than 500 kcal or more than 3,500 kcal for women.

Fracture assessment
About 5 years after completing the main questionnaire, surviving participants (n = 57,490) were mailed a follow-up questionnaire seeking updated information on diet, lifestyle, and health. A total of 38,027 (response rate: 66 percent) follow-up questionnaires were received. Participants were asked whether they had suffered any broken or fractured bones over the previous 6 years and to report the month and year of each fracture, the bone(s) affected, and the cause, categorized as fall (from any height), road traffic accident, other accident, fracture found only by radiograph examination, other, unspecified, or multiple causes. We defined an incident fracture as one involving bones other than the fingers, thumbs, toes, or ribs, of known year of occurrence, and occurring after the participant's date of recruitment. Fractures were assumed to have occurred on the first day of the month, with unknown month of fracture taken to be July if the reported year of occurrence preceded the year of completion of the follow-up questionnaire, and January otherwise.

Case and control selection
Cases and controls were selected from among participants who completed the follow-up questionnaire, who gave a blood sample, and who had at least one plasma aliquot remaining. Women who were pregnant at blood sampling or who were postmenopausal but reported that they were still menstruating at the time of blood sampling were excluded. Cases were participants who reported an incident fracture; up to two controls were matched to each case by sex, age at recruitment (within 72 months), date of blood sampling (within 30 days), duration of follow-up (within 24 months), and, for women, menopausal status (pre-, postmenopausal) and use of exogenous hormones (oral contraceptives or hormone replacement therapy) at blood sampling. Menstruating premenopausal women who were not taking oral contraceptives at the time of blood sampling were further matched on day of menstrual cycle (within 2 days). A total of 747 cases were identified, but plasma samples were unavailable for two cases, leaving a total of 745 cases and 1,454 controls.

Plasma 25-hydroxyvitamin D determination
The plasma 25-hydroxyvitamin D concentration was determined by enzyme immunoassay (OCTEIA 25-Hydroxy Vitamin D kit; Immunodiagnostic Systems, Limited, Bolton, Tyne and Wear, United Kingdom) in the Medical Research Council Human Nutrition Research laboratories in Cambridge. The intraassay coefficient of variation was 5.9 percent at 35 nmol/liter and 3.5 percent at 111 nmol/liter. The interassay coefficient of variation was 9.2 percent at 35 nmol/liter and 7.6 percent at 111 nmol/liter. Plasma 25-hydroxyvitamin D could not be assayed for 12 participants, leaving data on 730 cases and 1,445 matched controls for analysis.

Statistical analyses
Baseline characteristics of cases and controls were compared with chi-square tests of association for categorical variables and independent samples' t tests for continuous variables.

The geometric mean plasma 25-hydroxyvitamin D concentration in controls was calculated for a range of participant characteristics in men and women separately using multiple linear regression, adjusted for the interaction of month of blood draw and age at blood draw (categorized as 20–44, 45–54, 55–64, and ≥65 years). To assess the influence of month of blood draw on plasma levels, a multiple linear regression model was fitted that adjusted for the interaction of sex and age at blood draw.

Odds ratios as estimates of relative risks were calculated by use of conditional logistic regression models. Plasma 25-hydroxyvitamin D was divided into four categories (<50, 50–74, 75–99, and ≥100 nmol/liter) on the basis of proposed levels of vitamin D insufficiency (10, 11), and relative risks were calculated by use of the lowest category as reference. To investigate whether there was an association between average levels of plasma 25-hydroxyvitamin D and fracture risk, we calculated the concentrations adjusted for age and month of blood draw for men and women separately using a multiple linear model with age categorized into the same four groups as previously. Heterogeneity was assessed using a likelihood ratio test. Tests of trend were obtained by fitting the model to the logarithm (base 2) of plasma 25-hydroxyvitamin D concentration yielding the relative risk associated with a doubling in concentration.

Both unadjusted and multivariable-adjusted relative risks were calculated, with models being adjusted for method of recruitment (postal, general practitioner surgery); smoking; intakes of energy, calcium, and alcohol; body mass index; hours per week engaged in each of walking, cycling, other exercise/sport, and vigorous exercise; physical activity at work; marital status; and, for women only, parity and use of hormone therapy. Missing value categories were added to most of these variables in order to retain all of the observations in the analysis.

Subset analyses investigated fracture risk by plasma 25-hydroxyvitamin D concentration for matched sets in which the fracture was caused by a fall and for the two most common fracture sites, as well as for matched sets in which the case and controls were aged less than 55 years at blood draw and aged 55 years and over at blood draw. Heterogeneity between subsets was assessed using a chi-square test.

All analyses were performed using STATA, version 9.0, software (12), and all p values are two sided with p < 0.05 considered as significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Cases and controls were closely matched on most factors thought likely to influence fracture risk (table 1). There was some evidence that cases were more likely to exercise than controls: Statistically significant associations with case-control status were found for categories of walking among women (p < 0.01), cycling among men (p < 0.001), and vigorous exercise among women (p < 0.05). Male cases were less likely to be married or cohabiting (p < 0.05) and also had a somewhat higher alcohol intake, being 17.1 g/day for cases and 13.0 g/day for controls (p < 0.05). None of the other variables listed in table 1 was associated with case-control status. In particular, the mean plasma 25-hydroxyvitamin D concentration was almost identical for cases and controls (81.1 and 81.0 nmol/liter, respectively). The most common fracture site was the wrist/arm, accounting for 38 percent and 48 percent of the fractures in men and women, respectively (table 2). The second most common site was the ankle that, along with wrist/arm fractures, accounted for over 50 percent of all fractures in men and women. The most common cause of a fracture was a fall, which was responsible for 63 percent of fractures in men and 76 percent of fractures in women (table 2).


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  		TABLE 1. Characteristics of the study population according to sex and case/control status, EPIC-Oxford* study, United Kingdom, 1993–1999

 

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  		TABLE 2. Site and cause of first incident fracture in men and women, EPIC-Oxford* study, United Kingdom, 1993–1999

 
There was a clear late-summer peak in plasma 25-hydroxyvitamin D concentration among both cases and controls (figure 1). Adjusted geometric mean concentrations were at their lowest in the first 3 months of the year, with values around 60 nmol/liter, rising steadily to between 90 and 100 nmol/liter in August and September before falling again in the last 3 months of the year (figure 1). The mean concentrations were similar for cases and controls in each month. By use of a cutoff of 50 nmol/liter, 20 percent of men and 22 percent of women were classified as having a vitamin D insufficiency, while decreasing this cutoff to 25 nmol/liter (moderate-to-severe deficiency) results in only 2 percent of men and women being classified as deficient.


Figure 1
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  		FIGURE 1. Geometric mean plasma 25-hydroxyvitamin D by month of blood draw, EPIC-Oxford study, United Kingdom, 1993–1999. Means are geometric means and their corresponding 95% confidence intervals adjusted for sex, age at blood draw, and their interaction. Case means are depicted by solid circles and control means by open circles. EPIC-Oxford, European Prospective Investigation into Cancer and Nutrition-Oxford cohort. Jan, January; Feb, February; Mar, March; Apr, April; Jun, June; Jul, July; Aug, August; Sep, September; Oct, October; Nov, November; Dec, December.

 
Male and female controls had similar mean concentrations of plasma 25-hydroxyvitamin D after adjustment for age and month of blood collection, the average among men being 74.9 nmol/liter and among women, 72.1 nmol/liter. Associations between lifestyle factors and plasma 25-hydroxyvitamin D in male and female controls are shown in table 3. Age was strongly negatively related to plasma 25-hydroxyvitamin D in women but not in men (p < 0.001 and p = 0.265, respectively). There was significant heterogeneity between plasma 25-hydroxyvitamin D concentrations and body mass index among women, with those with the lowest and highest levels of body mass index having the lowest concentrations of 25-hydroxyvitamin D. A similar, nonsignificant, pattern was seen in men. Married women had a higher mean plasma 25-hydroxyvitamin D concentration than did unmarried women, and current users of hormone replacement therapy had a higher mean plasma 25-hydroxyvitamin D concentration than did both former users and never users (p = 0.003 and p < 0.001 for heterogeneity, respectively). There was no association between plasma 25-hydroxyvitamin D concentration and method of recruitment, smoking, or parity in women.


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  		TABLE 3. Associations between diet and lifestyle factors and plasma 25-hydroxyvitamin D (nmol/liter) in male and female controls, EPIC-Oxford* study, United Kingdom, 1993–1999

 
There were significant differences in mean plasma 25-hydroxyvitamin D by diet group (p < 0.001 for heterogeneity for both men and women), with vegetarians and vegans having noticeably lower mean concentrations than did nonvegetarians (table 3). Plasma 25-hydroxyvitamin D was positively associated with vitamin D intake in both men and women (p < 0.001 and p = 0.001 for linear trend, respectively). There was a significant increase in plasma 25-hydroxyvitamin D concentrations with increasing total energy intake for men only (p = 0.025); however, there was no association with calcium intake. The mean plasma 25-hydroxyvitamin D concentration increased with increasing level of alcohol intake for both men and women (p = 0.011 and p = 0.026, respectively).

Cycling, other exercise or sport, and vigorous exercise were each associated with plasma 25-hydroxyvitamin D in women (p = 0.025, p < 0.001, and p = 0.009 for linear trend, respectively), with a generally higher mean concentration in the most active women. There were no associations between plasma 25-hydroxyvitamin D and walking or physical activity at work. Similar nonsignificant patterns were also seen among men.

There was no evidence of an association between plasma 25-hydroxyvitamin D concentration and fracture risk for men or women (table 4). The unadjusted relative risks of a fracture associated with a doubling of plasma 25-hydroxyvitamin D concentration were 1.15 (95 percent confidence interval (CI): 0.82, 1.61) for men and 0.95 (95 percent CI: 0.80, 1.13) for women. Adjustment for factors associated with either 25-hydroxyvitamin D concentration or risk of fracture made little difference to the risk estimates. Using average plasma 25-hydroxyvitamin D concentrations corrected for month of blood draw did not materially alter the results (table 5).


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  		TABLE 4. Relative risk of fracture by plasma 25-hydroxyvitamin D in men and women, EPIC-Oxford* study, United Kingdom, 1993–1999

 

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  		TABLE 5. Relative risk of fracture by average plasma 25-hydroxyvitamin D corrected for month blood drawn in men and women, EPIC-Oxford* study, United Kingdom, 1993–1999

 
Restricting the analyses to those fractures caused by a fall or to the two most common fracture sites did not alter the risk estimates (results not shown). There was some evidence that the association between plasma 25-hydroxyvitamin D levels and risk of fracture was different according to age at blood draw; for women aged less than 55 years at blood draw, the relative risk for a doubling of 25-hydroxyvitamin D concentration was 1.03 (95 percent CI: 0.81, 1.30), while for women aged 55 years or more, this relative risk was 0.84 (95 percent CI: 0.65, 1.09), although these estimates were not significantly different (p = 0.264). Among men, this pattern was not seen; the relative risk for men aged less than 55 years was 1.15 (95 percent CI: 0.76, 1.75) and, for men aged 55 years or more, it was 1.13 (95 percent CI: 0.63, 2.03).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
In this large population-based cohort study of men and women, we find no evidence that plasma levels of 25-hydroxyvitamin D are related to risk of fracture, a result which is consistent across a number of subgroups including age at recruitment, site, and mechanism of fracture.

The levels of 25-hydroxyvitamin D found in the current study are higher than those reported in a recent population-based survey in the United Kingdom (13). In that survey, the average levels were around 50 nmol/liter in both men and women, with correspondingly higher proportions being classified as having vitamin D insufficiency (approximately 55 percent using a cutoff of 50 nmol/liter and 10 percent using a cutoff of 25 nmol/liter), the most likely cause for such differences being the variation between assays (14). Furthermore, this United Kingdom population survey did not observe the relation between plasma 25-hydroxyvitamin D concentrations and age in women seen in the current study, although their upper age limit was 64, and it is possible that any relation with age, if real, is apparent only in older women (15).

Dietary intake of vitamin D and diet group were strongly associated with plasma levels; vegans had the lowest level of 25-hydroxyvitamin D, reflecting their low intake of vitamin D (6). However, the proportion of variation in plasma 25-hydroxyvitamin D levels explained by dietary intake is very low (4.5 percent and 1.2 percent in men and women, respectively), with the major determinant of 25-hydroxyvitamin D in this population being age and exposure to ultraviolet radiation. This is demonstrated by the strong associations between 25-hydroxyvitamin D concentrations and age and month of blood collection (explaining 34.2 percent and 21.2 percent of the variation in men and women, respectively). We did not have detailed information on supplements containing vitamin D that participants were using at recruitment, so were unable to investigate whether there was an association between levels of 25-hydroxyvitamin D and supplement use or between supplement use and risk of fracture.

The majority of case-control studies report that levels of 25-hydroxyvitamin D are lower in fracture patients compared with controls (16–24), although others fail to find such an association (25, 26). However, there are few studies that have prospectively investigated the association between vitamin D status at recruitment and subsequent risk of fracture. The Study of Osteoporotic Fractures in the United States found that the serum 25-hydroxyvitamin D concentration was not associated with subsequent risk of hip or vertebral fracture, although a low level of 1,25-dihydroxyvitamin D was associated with a significantly increased risk for hip fracture (27). The Osteoporosis Prospective Risk Assessment (OPRA) study of elderly women found a significantly increased risk of fracture among those women whose 25-hydroxyvitamin D levels were less than 50 nmol/liter, although this was based on only nine fractures (28). In a study carried out in Finnish military recruits, low levels of serum 25-hydroxyvitamin D were associated with an increased risk of stress fracture (29). The reason for the difference in association between case-control studies and prospective studies is unclear but could be a consequence of a number of factors, for example: case selection since many studies used only hip fractures; the selection of the fracture-free populations since the hospital or institutionalized controls may have systematically different levels of vitamin D compared with population controls; and reverse causality where the fracture itself may have caused an alteration in vitamin D levels. However, the current study is consistent with previous prospective results and is, to the best of our knowledge, the largest prospective study to date among free-living healthy individuals.

In terms of bone health, low levels of vitamin D are often accompanied by a corresponding increase in parathyroid hormone levels to maintain calcium homeostasis, which results in an increase in bone turnover and a decrease in bone mineral density (1, 30, 31). However, the optimal level of vitamin D and the threshold below which a person can be viewed as being deficient remain controversial. A threshold of 50 nmol/liter was suggested as being representative of an insufficient level (32), although it has recently been suggested that 75 nmol/liter and possibly even higher may be necessary to minimize the deleterious health consequences in terms of both bone health and other diseases (10, 33). However, in the current study, there was no evidence that concentrations of 25-hydroxyvitamin D below 50 or 75 nmol/liter were associated with an increased risk of fracture. Future prospective studies should consider measuring 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, parathyroid hormone, and markers of bone turnover in order to investigate the overall effect of vitamin D on fracture risk.

Low levels of serum vitamin D have also been associated with muscle weakness and a higher risk of falls in elderly women (28, 34, 35), and a randomized trial has shown that vitamin D and calcium supplementation reduced the odds of falling among women (36). This higher rate of falls, muscular weakness, and lower bone mineral density all suggest that low levels of vitamin D should be associated with an increase in fracture risk. In the current study, we did not have any information on each participant's fall history, but participants were generally younger than in previous studies, and it is possible that those fractures that were not caused by a fall, normally some form of trauma, masked any relation. However, subset analyses by age at recruitment and restriction to those fractures caused by a fall (from an unknown height) did not provide evidence of an association between plasma 25-hydroxyvitamin D concentrations and fracture risk.

The main strength of the current study is its prospective nature. All information recorded at recruitment was prior to the fracture's occurrence and is therefore likely to be free from recall bias. It is of course possible that prior to recruitment some participants may have suffered a previous fracture and modified their lifestyle; however, as there is limited secondary prevention advice given following a fracture, we expect that the impact of this to be minimal. The main limitation of this study is that fractures were self-reported. However, self-report is reliable for several important fracture sites, including those of the hip, wrist, and humerus, and we excluded sites that are prone to poor reporting, specifically fractures of the fingers, thumbs, toes, and ribs (37). Moreover, the distribution of fractures seen in this population is similar to that previously reported for England and Wales (38). The use of self-reported fractures does prevent the capture of some osteoporotic fractures, in particular, nonclinical vertebral fractures. However, we have a range of other typically osteoporotic fractures, and analyses restricted to certain sites do not suggest any association between plasma 25-hydroxyvitamin D and fracture risk.

A problem with any observational study of vitamin D and fracture risk is the complicated interrelations between possible confounding variables. As seen in this study, exercise is associated with both an increase in vitamin D due to spending greater amounts of time outdoors and also an increased risk of fracture, most likely because of the greater risk of having an accident. Although adjustment for these possible confounders did not change the association between fracture risk and plasma 25-hydroxyvitamin D, we cannot rule out the possibility of residual confounding. Prevalent illness at recruitment is another possible confounder, and we have only the history of cardiovascular disease and diabetes. There are a number of other illnesses that can have an impact on either bone density or a participant's vitamin D status and, if the illness was more frequent in controls than cases, this could result in our estimated associations being weaker than the true associations. However, because of the predominantly young population where prevalence of illness is low, the impact of such unmeasured confounding is expected to be small. Assessment of the plasma 25-hydroxyvitamin D concentration was based on a single blood sample; however, this has been shown to be a reliable measure of exposure over a number of years (39), and fractures in the current study occurred within 5 years of blood sampling.

In summary, this study found no evidence of an association between plasma 25-hydroxyvitamin D and risk of fracture in either men or women.


   ACKNOWLEDGMENTS
 
The EPIC-Oxford study is supported by the Medical Research Council, United Kingdom, and by Cancer Research UK, United Kingdom. Rachel Neale is supported by a National Health and Medical Research Council, Australia, Sidney Sax postdoctoral fellowship.

Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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