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Extended report

Musculoskeletal pain is associated with very low


levels of vitamin D in men: results from the
European Male Ageing Study
John McBeth,1 Stephen R Pye,1 Terence W O’Neill,1 Gary J Macfarlane,2 Abdelouahid
Tajar,1 Gyorgy Bartfai,3 Steven Boonen,4 Roger Bouillon,5 Felipe Casanueva,6 Joseph
D Finn,1 Gianni Forti,7 Aleksander Giwercman,8 Thang S Han,9 Ilpo T Huhtaniemi,10
Krzysztof Kula,11 Michael E J Lean,9 Neil Pendleton,12 Margus Punab,13 Alan J Silman,1
Dirk Vanderschueren,14 Frederick C W Wu,15; EMAS Group

For numbered affiliations see ABSTRACT musculoskeletal pain. The vitamin D receptor has
end of the article Introduction A study was undertaken to test the been identified in muscle tissue4 and could explain
Correspondence to hypothesis that musculoskeletal pain is associated with the association with muscle weakness and regional
Dr John McBeth, ARC low vitamin D levels but the relationship is explained pain disorders5 such as low back pain. However,
Epidemiology Unit, University by physical inactivity and/or other putative confounding most reports have focused on the relationship
of Manchester, Oxford Road, factors. between vitamin D and CWP and have shown that
Manchester M13 9PT, UK; CWP is associated with low levels of vitamin D.6–8
Methods Men aged 40–79 years completed a postal
john.mcbeth@manchester.
ac.uk questionnaire including a pain assessment and attended Osteomalacia, a condition linked with very low
a clinical assessment (lifestyle questionnaire, physical levels of vitamin D of which widespread musculo-
Accepted 11 December 2009 performance tests, 25-hydroxyvitamin D3 (25-(OH) skeletal pain is a feature, could explain that rela-
D) levels from fasting blood sample). Subjects were tionship. However, the available data are equivocal
classified according to 25-(OH)D levels as ‘normal’ with reports of no difference in vitamin D levels
(≥15 ng/ml) or ‘low’ (<15 ng/ml). The relationship when subjects with diffuse pain were compared
between pain status and 25-(OH)D levels was assessed with subjects with osteoarthritis,9 and lower lev-
using logistic regression. Results are expressed as ORs els in women but not in men with CWP.10 There
and 95% CIs. are a number of possible reasons why these differ-
Results 3075 men of mean (SD) age 60 (11) years ences have been observed. Varying cut-offs have
were included in the analysis. 1262 (41.0%) subjects been used to define ‘low’ or ‘insufficient’ vitamin D
were pain-free, 1550 (50.4%) reported ‘other pain’ that levels, although levels of ≤20 ng/ml that correspond
did not satisfy criteria for chronic widespread pain (CWP) to physiological insufficiency are commonly used.
and 263 (8.6%) reported CWP. Compared with patients Also, variation in control subjects or a lack of a
who were pain-free, those with ‘other pain’ and CWP had control group makes it difficult to interpret results.
lower 25-(OH)D levels (n=239 (18.9%), n=361 (23.3) However, the most important problem to date has
and n=67 (24.1%), respectively, p<0.05). After adjusting been the lack of control for factors that may explain
for age, having ‘other pain’ was associated with a 30% the observed relationships. Low levels of physical
increase in the odds of having low 25-(OH)D while CWP activity,11 depression in older subjects12 and smok-
was associated with a 50% increase. These relationships ing13 are associated with low vitamin D levels.
persisted after adjusting for physical activity levels. These factors are also associated with the presence
Adjusting for additional lifestyle factors (body mass index, of CWP, and it is possible that they may explain
smoking and alcohol use) and depression attenuated some, if not all, of the observed associations.
these relationships, although pain remained moderately While it is plausible that low vitamin D levels
associated with increased odds of 20% of having low could be causally related to CWP via osteomalacia,
vitamin D levels. the prevalence of osteomalacia could not explain
Conclusions These findings have implications at a the high prevalence of CWP in the general popu-
population level for the long-term health of individuals lation. It is equally plausible that CWP leads to
with musculoskeletal pain. low vitamin D levels, possibly via reduced levels
of physical activity and consequent reduced expo-
sure to sunlight. In the current study we tested the
INTRODUCTION hypothesis that the presence of CWP would predict
Musculoskeletal pain problems are one of the major lower levels of vitamin D. The secondary hypoth-
global causes of disability and one of the most esis was that any observed relationship would be
common reasons for primary care consultation.1 explained by low levels of physical activity and/or
Musculoskeletal pain is common with, for example, other putative lifestyle and psychological confound-
approximately 33%2 and 10%3 of the general pop- ing factors.
ulation reporting low back pain and chronic wide-
spread pain (CWP), respectively. Despite extensive METHODS
investigations over the past 20 years, the aetiology Subjects
of these disabling pain disorders remains unclear. The subjects included in this analysis were recruited
Vitamin D may be associated with the presence of for participation in the European Male Ageing

1448 Ann Rheum Dis 2010;69:1448–1452. doi:10.1136/ard.2009.116053


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Extended report

Study (EMAS). Details regarding recruitment, response rates (DiaSorin; Stillwater, Minnesota, USA). Intra- and inter-assay
and assessments have been described previously.14 Briefly, 3369 coefficients of variation for 25-(OH)D were 11% and 9%,
men were recruited from population-based sampling frames in respectively. The detection limit of the radioimmunoassay kit
eight centres: Florence (Italy), Leuven (Belgium), Lodz (Poland), was 1.5 ng/ml 25-(OH)D.
Malmo (Sweden), Manchester (UK), Santiago del Compostella
(Spain), Szeged (Hungary) and Tartu (Estonia). Stratified random Analysis of data
sampling was used with the aim of recruiting equal numbers of The significance of any observed differences in age and
men in each of four 10-year age bands: 40–49, 50–59, 60–69 and other continuous variables between those with ‘other pain’
≥70 years. Subjects were invited by letter to complete a short or CWP compared with those who were pain-free were
postal questionnaire and attend a local clinic for further screen- determined using t tests, while χ2 tests were used for categori-
ing. The study was funded by the European Union and ethical cal variables. Vitamin D deficiency has been defined variably
approval for the study was obtained in accordance with local as a level <10–20 ng/ml.23 24 In our study the frequency of
institutional requirements in each centre. CWP appeared if anything to increase at values <15 ng/ml (see
figure 1); based on this, we classified subjects as ‘low’ vitamin
Assessments D if the level was <15 ng/ml and ‘higher’ if the level was above
The short postal questionnaire included items concerning health this. The physical performance tests and PASE scores were
and lifestyle information. Subjects were asked about current treated as continuous variables. Body mass index (BMI) was
smoking (response: yes/no), alcohol consumption in the previ- calculated as weight in kilograms divided by height in metres
ous year (response: every day/5–6 days per week/3–4 days per squared. Scores of 0–9 on the BDI indicate that a person is
week/1–2 days per week/less than once a week/not at all) and not depressed, 10–18 indicates mild to moderate depression,
time spent exercising (walking or on a bicycle) out of doors each 19–29 indicates moderate to severe depression and 30–63 indi-
day (response: none/<30 min/30 min to 1 h/>1 h). Those who cates severe depression. For the purpose of the current analy-
agreed to participate subsequently attended a hospital research sis, subjects were classified as ‘depressed’ (BDI score 10–63) or
clinic to complete an interviewer-assisted questionnaire (IAQ). ‘not depressed’ (score 0–9).
The IAQ included the Physical Activity Scale for the Elderly Logistic regression was used to determine the association
(PASE),15 which is a measure of participation in activities (sit- between pain and 25-(OH)D status as the dependent variable.
ting, walking, light, moderate, or strenuous sport or recreational The relationships were cumulatively adjusted for age and sea-
activity, strength or endurance exercises, light or heavy house- son during which the blood sample was collected, physical
work/gardening) in the past 7 days with higher scores reflecting activity and other putative confounding factors. Evidence of sta-
higher levels of activity. The IAQ also included the 21-item Beck tistical interaction between pain status and all other variables
Depression Inventory (BDI) to measure the presence and sever- with 25-(OH)D status as the outcome variable was explored.
ity of depressive symptoms.16 In addition, physical performance The comparison group for all analyses were those subjects
was assessed during the clinic visit by measuring the time in reporting no pain. The results are expressed as ORs and 95%
seconds taken to go from a sitting to a standing position17 and CIs. Statistical analysis was performed using STATA Version 9.2
measuring the time in seconds taken to walk 50 feet.18 Height (http://www.stata.com).
and weight were measured in a standardised fashion.
RESULTS
Ascertainment of pain Of the 3369 participants, 3075 (91.3%) provided full data on
Information on pain was collected in the postal questionnaire pain status and had their 25-(OH)D levels measured. In the total
by asking subjects: ‘In the past month have you had any pain sample the mean (SD) level of 25-(OH)D was 25.0 (12.7) ng/ml.
which has lasted for one day or more?’ If subjects answered A total of 1262 (41.0%) reported no pain in the past month, 1550
positively they were asked to indicate the site(s) of pain on (50.4%) reported ‘other pain’ and 263 (8.6%) reported pain that
four-view body manikins. To assess chronicity, subjects were satisfied the ACR criteria for CWP. Subjects with ‘other pain’ and
asked whether they had been aware of the pain for 3 months or CWP had significantly lower mean 25-(OH)D levels than those
more. Three groups of subjects were identified: those reporting
no pain, those reporting ‘other pain’ that did not satisfy criteria
for CWP and those with CWP. In classifying CWP, the criteria
included in the American College of Rheumatology (ACR) cri-
teria for fibromyalgia19 were used. These criteria require pain
lasting at least 3 months, both above and below the waist, on
the right and left sides of the body and in the axial skeleton.
These methods for collecting and classifying pain information
have been used frequently in population studies and construct
validity has been demonstrated.20 21 Further details have been
reported previously.22

25-Hydroxyvitamin D3 assay
A single fasting morning (before 10:00) venous blood sample
was obtained from all subjects. Serum was separated imme-
diately after phlebotomy, stored at −80°C and shipped on dry
ice to a single laboratory (University of Leuven) for measure-
ment of 25-hydroxyvitamin D3 (25-(OH)D). Serum 25-(OH)D Figure 1 Prevalence of chronic widespread pain (CWP) by
levels were determined using an equilibrium radioimmunoassay 25-hydroxyvitamin D3 (25-(OH)D) level.

Ann Rheum Dis 2010;69:1448–1452. doi:10.1136/ard.2009.116053 1449


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Extended report

who were pain-free (24.8 (12.9) ng/ml and 23.9 (11.8) ng/ml performance measures, having ‘other pain’ and CWP remained
vs 25.6 (12.5) ng/ml, p<0.05). As shown in table 1, a significantly independently associated with low 25-(OH)D.
higher proportion of subjects with ‘other pain’ (23.2%) and CWP We then adjusted for other putative confounders. Smoking,
(25.5%) were classified as ‘low’ 25-(OH)D compared with those alcohol use and depression were all associated with the out-
reporting no pain (18.6%). There were no significant differences come. After adjusting for these variables, both ‘other pain’
in age or BMI between subjects with low and higher 25-(OH)D (OR 1.2, 95% CI 1.01 to 1.5) and CWP (OR 1.2, 95% CI 0.9
(table 1). However, self-reported physical activity in the past to 1.8) remained moderately associated with low 25-(OH)D,
week, PASE score and the two physical performance measures although the relationship with CWP was no longer statistically
were significantly associated with low 25-(OH)D. Similarly, significant.
subjects who currently smoked cigarettes and those who were
depressed were more likely to have low 25-(OH)D. The rela- DISCUSSION
tionship between alcohol use in the past week and 25-(OH)D The aim of this study was to determine whether, in a general
status was a U-shaped curve: subjects who reported alcohol use population sample of middle-aged men, reporting musculo-
for 3–4 days in the past week were least likely to be classified as skeletal pain would be associated with low levels of vitamin D
low 25-(OH)D while those reporting 0–2 days or 1–7 days were (measured by 25-(OH)D)). After adjusting for age, subjects clas-
more likely. sified as having ‘other pain’ and those with CWP had a mod-
After adjustment for age and season of blood sample collec- erately increased odds of low 25-(OH)D. These relationships
tion, subjects with ‘other pain’ were 30% (OR 1.3, 95% CI 1.1 to persisted after adjusting for measures of physical activity and
1.6) more likely to have low 25-(OH)D than those reporting no physical performance and other factors that may have con-
pain (table 2). This relationship was slightly more marked among founded the relationship including BMI, smoking, alcohol use
subjects with CWP who were 40% (OR 1.4, 95% CI 1.1 to 2.1) and depression. These data suggest that, although the relation-
more likely to have low 25-(OH)D. When the physical activity ship between CWP and vitamin D status is partially explained
measures were included in the analysis, self-reported activity of by the additional factors associated with pain, there remains a
≥30 min in the past week was protective against low 25-(OH)D moderate association with pain per se. The current study was
levels. Similarly, a higher PASE score, indicating increased levels cross-sectional and the true direction of causality is unclear. It is
of activity, was associated with a decreased likelihood of having equally plausible that low vitamin D predicts the onset of CWP.
low 25-(OH)D levels. Of the objective physical assessments, an The nature of the CWP and vitamin D relationship can only be
increased time to walk 50 feet was associated with an increased fully elucidated in a prospective study.
odds of having low 25-(OH)D. After adjusting for these physical Our study has a number of strengths: it was a large popula-
tion-based study that used standardised well-validated instru-
Table 1 Subject characteristics by vitamin D status ments to assess pain and putative confounders. A number of
subjects who were invited to participate in the study did not
25-(OH)D status
do so. Of those who did participate, a proportion (N=294) did
Higher (≥15 ng/ml), Low (<15 ng/ml),
N=2414 (78.5%) N=661 (21.5%) not provide pain data or a blood sample for assaying 25-(OH)
Pain status (N (%))
D levels. It is possible that the prevalence of pain and levels
No pain 1027 (81.4) 235 (18.6) of vitamin D may not reflect the true levels in the popula-
Other pain 1191 (76.8) 359 (23.2) tions from which the study sample was drawn. However, this
CWP 196 (74.5) 67 (25.5)† should not affect the results of the analysis which is based on
Physical activity measures an internal comparison of responders. One of the main limi-
Self-reported activity duration in past week (N (%)) tations in interpreting the data is the cross-sectional design
None 277 (72.5) 105 (27.5) and the difficulty in determining the temporal nature of the
<0.5 h 497 (74.3) 172 (25.7) relationships for which prospective studies are required. It is
0.5–1 h 860 (80.5) 209 (19.6)
possible, for example, that patients with CWP may alter their
>1 h 769 (81.8) 171 (18.2)*
lifestyle with resulting reduced exposure to sunlight which
PASE score (range 0–1100) 200.4 (91.0) 179.1 (91.8)†
Time taken to walk 50 feet (s) 13.4 (3.1) 14.1 (4.1)†
is the major source of vitamin D levels. Also, in the current
Time taken from sitting to standing (s) 12.6 (4.4) 13.0 (5.0)† analyses we have treated variables such as physical activity
Age and lifestyle measures and smoking as putative confounders. Of course it may be the
Age at interview (years) 60.0 (11.0) 59.4 (11.1) case that these variables are part of a pathway to developing
BMI (kg/m2) 27.6 (3.8) 27.9 (4.8) pain; it is plausible that low levels of physical activity lead
Current smoker (N (%)) to vitamin D deficiency which, in turn, leads to widespread
No 1968 (81.6) 443 (18.4) body pain. Including such factors in our multivariate models
Yes 429 (66.9) 212 (33.1)* may mean we have ‘overadjusted’ the observed relationships.
Alcohol use, number of days in past week (N (%))
Again, the nature of these relationships will be more trans-
None 364 (73.7) 130 (26.3)
parent in prospective studies. Finally, the data refer to a pre-
1–2 1160 (78.6) 315 (21.4)
3–4 316 (82.9) 65 (17.1)
dominantly Caucasoid European population and extrapolation
5–6 171 (79.2) 45 (20.8) beyond this should be undertaken with caution.
7 390 (79.3) 102 (20.7)* The results of previous clinic and population studies provide
Depressed (N (%)) somewhat conflicting data concerning the relationship between
No 1895 (80.3) 464 (19.7) vitamin D levels and CWP. In a population-based study that
Yes 475 (71.9) 186 (28.1)* included men and women,10 25-(OH)D status was found to be
All values are mean (SD) unless otherwise indicated. associated with CWP in women only. However, the relation-
*χ2 test, p<0.05. ship among women was unclear; after adjustment for confound-
†t test, p<0.05.
BMI, body mass index; CWP, chronic widespread pain; 25-(OH)D, 25-hydroxyvitamin ing factors there was no linear relationship between vitamin D
D3; PASE, Physical Activity Scale for the Elderly. status and reporting CWP. Only women with 25-(OH)D

1450 Ann Rheum Dis 2010;69:1448–1452. doi:10.1136/ard.2009.116053


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Extended report

Table 2 Relationship between pain status and low (<15 ng/ml) 25-hydroxyvitamin D3 (25-(OH)D) levels
Adjustments
Age and season + Physical activity + Lifestyle factors
Pain status
No pain Referent Referent Referent
Other pain 1.3 (1.1 to 1.6) 1.3 (1.05 to 1.6) 1.2 (1.01 to 1.5)
CWP 1.5 (1.1 to 2.1) 1.4 (1.01 to 2.0) 1.2 (0.9 to 1.8)
Physical activity measures
Self-reported activity duration in past week
None Referent Referent
<0.5 h 0.9 (0.6 to 1.2) 0.9 (0.7 to 1.3)
0.5–1 h 0.6 (0.5 to 0.9) 0.7 (0.5 to 0.95)
>1 h 0.7 (0.5 to 0.9) 0.7 (0.5 to 0.9)
PASE score 0.997 (0.996 to 0.998) 0.997 (0.996 to 0.999)
Time taken to walk 50 feet 1.08 (1.05 to 1.1) 1.06 (1.03 to 1.1)
Time taken from sitting to standing 0.99 (0.97 to 1.02) 0.99 (0.97 to 1.02)
Lifestyle measures
BMI (kg/m2) – 1.02 (0.995 to 1.04)
Current smoker
No – Referent
Yes – 2.1 (1.7 to 2.7)
Alcohol use (number of days in past week)
None – 2.0 (1.3 to 2.9)
1–2 – 1.4 (0.997 to 1.9)
3–4 – Referent
5–6 – 1.5 (0.9 to 2.4)
7 – 1.5 (0.99 to 2.1)
Depressed
No – Referent
Yes – 1.3 (1.1 to 1.7)
All values are OR (95% CI).
Subjects with ‘higher’ (≥15 ng/ml) 25-(OH)D levels were the comparison group.
BMI, body mass index; CWP, chronic widespread pain; PASE, Physical Activity Scale for the Elderly.

levels between 10.4 and 20.4 ng/ml (compared with those with within groups did not differ (osteoarthritis 20%, diffuse pain
30–40 ng/ml) were significantly more likely to report CWP while 29%; p=0.09). The data confirm an association with vitamin D
those with 25-(OH)D levels of <10.4 ng/ml were not. No rela- that is partially explained by other factors, particularly smoking,
tionship was evident for men, even before adjustments were alcohol and depression.
made for putative confounders. There were some differences in What are the clinical implications of these findings? It has
mean 25-(OH)D levels between that study and ours: subjects been suggested that all patients with CWP should be screened
without CWP in the current study had higher levels (25.6 ng/ ml for low levels of vitamin D,8 but that is likely to be expensive.27
vs 21.4 ng/ml), although mean levels in subjects with CWP A small trial that identified patients with fibromyalgia with lev-
were similar in both studies (23.9 ng/ml vs 21.3 ng/ml). In stud- els of 25-(OH)D between 9 and 20 ng/ml randomised 25 patients
ies of clinic patients with fibromyalgia, up to half6 7 or all8 par- to treatment with placebo and 25 patients to treatment with
ticipants have been reported to have ‘low’ (<50 and <20 ng/ml, vitamin D2 (ergocalciferol) 50 000 IU once per week.9 Three
respectively) serum 25-(OH)D. 25-OHD levels were also lower months later mean 25-(OH)D levels had significantly improved
in patients with fibromyalgia than in patients with other rheu- in those receiving the active treatment (31.2 ng/ml) compared
matic disorders including osteoporosis.25 In a population study with those in the placebo group (19.3 ng/ml), although there was
of UK women of South Asian origin, low (<10 ng/ml) 25-(OH)D no improvement in pain or pain-related functional ability. These
was more common among those with widespread pain than in data contribute to the hypothesis that vitamin D insufficiency is
those reporting no pain. Osteomalacia, one consequence of low unlikely to be causally related to CWP and is likely to be a marker
vitamin D, could explain the presence of widespread pain. We for other factors that are associated with pain such as smoking,
do not have information that would allow us to assess directly alcohol use and depression. Nevertheless, irrespective of the ori-
whether the prevalence of osteomalacia was higher in those gin of the low levels of vitamin D, the long-term implications for
with CWP than in the pain-free group. However, we did exam- low bone density and poor general health among patients with
ine levels of serum calcium and found no significant differences CWP are clear. Musculoskeletal pain is one of the most common
(mean (SD) mg/dl: no pain 2.4 (0.1) and CWP 2.4 (0.1), p=0.07). reasons for consultation to primary care. In 2007, the consul-
Similarly, we found no difference in levels of serum parathor- tation rate for musculoskeletal and connective tissue disorders
mone (mean (SD) ng/ml: no pain 28.6 (13.8) and CWP 29.4 (15.4), (International Classification of Diseases (ICD) codes 710–739)
p=0.38), high levels of which are associated with secondary bone was 1691 per 10 000, which equates to 8 800 288 consultations
pain. In a study of clinic patients with fibromyalgia, vitamin D in England and Wales (http://www.rcgp.org.uk/pdf/BRU%20
deficiency (25-(OH)D <10 ng/ml) was associated with anxiety Annual%20prevalence%20report%202007.pdf).
and depression.26 Compared with subjects with osteoarthritis, The current findings would suggest that those who present
those with diffuse pain were found to have almost identical with additional factors of smoking, alcohol use or depression
25-OHD levels (29.2 and 28.8 ng/ml, respectively).9 In that study should be screened for low vitamin D levels and supplemented
the proportion of subjects with ‘insufficient’ levels (≤20 ng/ml) appropriately.

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Extended report

The EMAS Study Group Florence (Gianni Forti, Luisa Petrone, Antonio Cilotti); 4. Simpson RU, Thomas GA, Arnold AJ. Identification of 1,25-dihydroxyvitamin D3
Leuven (Dirk Vanderschueren, Steven Boonen, Herman Borghs); Lodz (Krzysztof receptors and activities in muscle. J Biol Chem 1985;260:8882–91.
Kula, Jolanta Slowikowska-Hilczer, Renata Walczak-Jedrzejowska); London (Ilpo 5. Macedo JA, Hesse J, Turner JD, et al. Glucocorticoid sensitivity in fibromyalgia
Huhtaniemi); Malmö (Aleksander Giwercman); Manchester (Frederick Wu, Alan patients: decreased expression of corticosteroid receptors and glucocorticoid-induced
Silman, Terence O’Neill, Joseph Finn, Philip Steer, Abdelouahid Tajar, David Lee, leucine zipper. Psychoneuroendocrinology 2008;33:799–809.
Stephen Pye); Santiago (Felipe Casanueva, Marta Ocampo, Mary Lage); Szeged 6. Huisman AM, White KP, Algra A, et al. Vitamin D levels in women with systemic
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(Min Jiang). 7. Al-Allaf AW, Mole PA, Paterson CR, et al. Bone health in patients with fibromyalgia.
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Acknowledgements The authors thank the men who participated in the eight
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Competing interests None.
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Provenance and peer review Not commissioned; externally peer reviewed.
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1452 Ann Rheum Dis 2010;69:1448–1452. doi:10.1136/ard.2009.116053


Downloaded from http://ard.bmj.com/ on June 24, 2015 - Published by group.bmj.com

Musculoskeletal pain is associated with very


low levels of vitamin D in men: results from
the European Male Ageing Study
John McBeth, Stephen R Pye, Terence W O'Neill, Gary J Macfarlane,
Abdelouahid Tajar, Gyorgy Bartfai, Steven Boonen, Roger Bouillon,
Felipe Casanueva, Joseph D Finn, Gianni Forti, Aleksander Giwercman,
Thang S Han, Ilpo T Huhtaniemi, Krzysztof Kula, Michael E J Lean, Neil
Pendleton, Margus Punab, Alan J Silman, Dirk Vanderschueren,
Frederick C W Wu and EMAS Group

Ann Rheum Dis 2010 69: 1448-1452 originally published online May 24,
2010
doi: 10.1136/ard.2009.116053

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