Background
Musculoskeletal pain (MSP) is a leading cause of morbidity and presentation to primary care [
1‐
4]. In the United Kingdom, 37 % of women and 31 % of men report some kind of chronic pain [
5] and approximately 10 % report chronic widespread pain (CWP) [
3]. The aetiology of CWP is complex and somewhat poorly understood though both physical and psychological factors have been associated with its development [
6‐
12].
Osteomalacia, a disorder due to profound vitamin D deficiency, is associated with widespread musculoskeletal pain. It remains unclear whether less severe forms of deficiency are also linked with musculoskeletal pain. Vitamin D is obtained either from diet or by synthesis in the skin following UVB light exposure. Prior to becoming biologically active it undergoes two hydroxylations, firstly to 25-hydroxyvitamin D (25-(OH) D) and subsequently to the biologically active form, 1,25 dihydroxyvitamin D (1,25-(OH)
2D. 25-(OH) D has a long half-life and is used as an indicator of vitamin D status [
13].
Results of observational studies assessing the relationship between vitamin D and musculoskeletal pain are somewhat inconsistent, with some, though not all, reporting a significant association between low vitamin D and CWP in specific groups [
8,
14,
15]. Similarly in fibromyalgia, a sub-type of CWP, some studies suggest an association with vitamin D deficiency [
16,
17] whilst others do not [
18,
19]. Using cross-sectional data from the baseline arm of the European Male Ageing Study (EMAS), a multicentre cohort study designed to assess the incidence and prevalence of a range conditions associated with male ageing, we reported an association between CWP and low vitamin D in men at baseline, though the effect was attenuated after adjustment for age, physical activity level, lifestyle factors and depression [
15]. There are to our knowledge, however, no data from prospective studies. Experimental studies assessing the effects of vitamin D supplementation on patients’ chronic pain results are also conflicting: a Cochrane review, incorporating trials assessing the effects of vitamin D supplementation on participants with and without vitamin D deficiency, found insufficient evidence of a role for vitamin D supplementation in the treatment of chronic pain [
20]. Thus the link between low vitamin D and CWP remains uncertain.
Using data from the prospective arm of EMAS, the aim of this study was to determine i) whether low vitamin D levels were associated with an increased risk of developing CWP in those without CWP, ii) whether low vitamin D was linked with changes in number of reported painful sites and iii) whether any of the apparent associations could be explained by adverse lifestyle or health factors.
Discussion
In this analysis, compared to those in the upper quintile of serum 25 (OH) D level men in the lowest quintile (<15.6 ng/mL) at baseline were more likely to have developed CWP at follow up though this appeared to be related to the presence of adverse health factors, particularly obesity and depression. No significant association was observed between 1,25 (OH) 2D and the new occurrence of CWP.
Some previous observational and experimental studies have suggested that low levels of vitamin D may have a causal role in the development of chronic pain, though the evidence is conflicting [
20]. We however observed, after adjustment, no independent association between vitamin D at baseline and CWP at follow up in our male, and largely Caucasian, population and our results are in keeping with previous studies which have found no association either at all or not in men [
8,
15,
18], though a significant association has been reported previously in women [
8]. There is also some evidence of ethnic variation in the prevalence of CWP with higher rates observed in non-caucasians [
14,
34] and in some ethnic groups, such as British residents of South Asian ethnic origin the prevalence of both vitamin D deficiency and CWP are significantly increased [
14]. It is therefore possible that whilst we did not observe an independent association between low vitamin D and the development of CWP in our population the pathogenesis of CWP may be different in specific groups, and in some this may include low vitamin D.
We also assessed the association 1,25-(OH)
2D, the biologically active form of vitamin D and CWP. We observed a trend towards an increased risk of CWP for those in the lowest quintile of 1,25-(OH)
2D, though in contrast to our findings with 25-(OH) D, even in the unadjusted analysis this did not reach statistical significance. 1,25-(OH)
2D has a short half-life and the serum level is dependent on a range of other factors including serum phosphate, calcium and parathyroid hormone levels. Current guidance recommends 1,25-(OH)
2D is not useful in determining the vitamin D status of patients [
31] and therefore this measure likely poorly reflects the vitamin D status of our population.
Approximately half of the study participants at either baseline or follow up reported experiencing some pain, though did not meet the criteria for CWP. This is a heterogeneous group ranging from those with localised pain to those almost meeting the criteria for CWP. It seems unlikely, however, that inclusion or reclassification of those with more severe pain (within the ‘some pain’ group) would have influenced the findings.
In our population 8.4 % and 9.6 % of participants met the criteria for CWP at baseline and follow up respectively, which is higher than the prevalence of CWP previously reported in community-dwelling men [
3,
4]. We observed significant changes in pain status between baseline and follow up with some 42.4 % of participants changing pain status which is broadly consistent with findings from other studies [
35,
36].
We observed a strong association between depression, the presence of which was determined using the BDI, and CWP. This has been observed in other studies and is consistent with reports of the NHANES-1 cohort [
37] in the USA which found depression predicted the risk of developing chronic musculoskeletal pain. We also observed that increased BMI was a predictor of CWP in keeping with the co-occurrence of CWP and raised BMI reported previously [
38], although this is the first prospective study to demonstrate a link. Smoking and alcohol consumption were not however linked with CWP in contrast to previous reports [
39].
There are a number of limitations which need to be considered in interpreting our data. The participation rate for the baseline survey was 41 % of those invited to take part. There were significant differences between those who participated in the full study (
N = 3369) and those who returned the initial postal questionnaire only (
N = 594), most relevant of which was the prevalence of pain. 59.4 % of full study participants reported pain lasting one day or more in the preceding month at baseline compared to 43.8 % of those who returned the questionnaire only [
21]. Such potential selection factors mean that caution is needed in interpreting the absolute prevalence of pain observed, however, they are unlikely to have influenced our main findings of a link between CWP and vitamin D which were based on an internal comparison of those recruited. In our study pain status was assessed prospectively after an interval of 4.3 years following assessment of vitamin D. Any change in vitamin D status during that time would result in misclassification of D status and reduce the likelihood of findings significant associations. In a study though of postmenopausal women there was only moderate intra-individual variation in serum 25-(OH) D between baseline and follow up at 5 years and the authors supported the use of single point measurement of vitamin D in prospective studies with follow up periods less than 5 years [
40]. Vitamin D is synthesised in the skin, dependant on skin type and levels of UVB exposure, however, we did not have any information about these factors in our data, and were not therefore able to make adjustment for them. There is also variation in levels of D during the year with higher levels during the summer months–we observed however no association between CWP and season (data not shown) and so did not make any adjustment for season. It is also possible that any effect of vitamin D on the development of CWP occurs through a mediator variable, such as depression [
41], which we treated as a confounder and adjusted for in our analysis thereby potentially masking a true association. Additionally, physical activity and performance was assessed using the PASE score, time to stand from sitting and also time to walk 50 feet. Though widely used, these tests have not been validated across the entire age range included in this study. Finally the men who contributed data to this analysis were predominantly European and Caucasian and the results should be extrapolated beyond this with caution.
Acknowledgements
The study was supported by the Commission of the European Communities Fifth Framework Program: ‘Quality of Life and Management of Living Resources’ [grant QLK6-CT-2001-00258]. Support was also provided by Arthritis Research UK [Grant 20380] and the National Institute of Health Research (NIHR) Manchester Musculoskeletal Biomedical Research Unit. PSM is an NIHR supported academic clinical fellow. The views expressed in this publication are those of the author (s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. DV is a senior clinical investigator supported by the Clinical Research Fund of University Hospitals Leuven, Belgium.
The EMAS Study Group: Florence (Gianni Forti, Luisa Petrone, Antonio Cilotti); Leuven (Dirk Vanderschueren, Steven Boonen, Herman Borghs); Lodz (Krzysztof Kula, Jolanta Slowikowska-Hilczer, Renata Walczak-Jedrzejowska); London (Ilpo Huhtaniemi); Malmö (Aleksander Giwercman); Manchester (Frederick Wu, Alan Silman, Terence O’Neill, Joseph Finn, Philip Steer, Abdelouahid Tajar, David Lee, Stephen Pye); Santiago (Felipe Casanueva, Marta Ocampo, Mary Lage); Szeged (Gyorgy Bartfai, Imre Földesi, Imre Fejes); Tartu (Margus Punab, Paul Korrovitz); Turku (Min Jiang)
Competing interests
The authors declare they have competing interests.
Authors’ contributions
EMAS Study concept: FCW, ITH. EMAS Study Design: FCW, JDF Acquisition of data: FCW, JDF, GB, FC, GF, AG, KK, NP, MP, DV, RB, SB. Interpretation of data: PSM, FCW, JDF, TWO, SRP, JM, FC, DML, AT, NP Drafting of manuscript: PSM, TWO. All authors contributed to the revision of, and approved the final manuscript.