Vitamin D and non-specific musculoskeletal complaints in non-Western immigrants

Several investigators found an association between low serum-vitamin D levels
and musculoskeletal complaints (Plotnikoff 2003, Erkal 2006, Mouyis 2008) and
muscle strength (Glerup 2000, Biss-Ferr 2004, Ward 2009), though others did not
(Helliwell 2006, Reed 2007). Anyhow, many observational studies (case-reports
as well as intervention studies) report a beneficial effect of vitamin D
supplementation on musculoskeletal diseases or complaints. Some reported this
in one to six weeks, (Gloth, 91 Prabhala ,00 Badsha 09 Grootjan 02) but longer
intervals are reported too (de la Torrente 04, Nellen 96 Glerup 00, Al Farraj
03). Moreover, vitamin D supplementation proved to enhance muscle strength
(Glerup 00,Dhesi 04, Bishoff-Ferrari 04 ,Lips 10,Ward 10). In a systematic
review Straube could find no proof for a positive effect on musculoskeletal
complaints of this therapy. (Straube / Cochrane2010).
After this review three randomized controlled trials (RCT) on this subject were
published: one did not prove pain-relieving effect of vitamin D3 (2 x 10E5 IU
or 800 IU/d) in six months in vitamin D-deficient non-Western immigrants
(18-65yr). However, this study was not designed to evaluate pain-modifying
effect of vitamin D (Wicherts, 2010). Another was done in Turkish elderly, who
did not get relief from 300.000 IU vitamin D3 in 4 weeks. (Sakalli, 2011). The
third one was done by our group: 84 non-western immigrants, included with low
25-OH-D levels and > 3 months pain, were successfully treated for 6 weeks with
150.000 IU; a better effect after 12 weeks was suggested (Schreuder 2012).
A direct effect of vitamin D on muscle cells has pathological ground: muscle
cells have *like many other tissues- vitamin D receptors (Simpson 1985,
Bischoff, 2001 Ceglia 2008). Also enhancement of mood as an indirect effect on
complaints could be an explanationIn a systematic review and meta-analysis
(Anglin, 2013) an association of depression and low 25-OH-D levels was found in
10 cross-sectional studies, but also in 3 cohort-studies in the elderly: people
with 25-OH-D > 75 nmol/L were less prone to develop depression, though an
effect of having levels < 50 nmol/L could not reliably determined in that
study. Three intervention-studies for depression were published only after this
analysis: after 6 months of supplementation (40.000 IU/wk) no improvement of
depressive symptoms was found in a RCT in healthy volunteers, whether with high
or low 25-OH-D levels (Kjaergard, 2012). In a second RCT in 40 patients with
depression fluoxetine with 1500 IU/d vitamin D had better effect on depression
than fluoxetine only (Khoraminya, 2012). In a third (not blinded) trial in
depressed patients with low levels of 25-OH-D got 150.000 IU or 300.000 IU
vitamin D or placebo. After three months the treated groups improved 5 resp, 7
points on the Beck Depression Index (Mozzafari, 2013) Non-Western immigrants
in Western Europe are prone to vitamin D deficiency (Shaunak 1985, Bergman
2001, Erkal 2006, Wielders 2006, Hirani 2009) and also more often have
musculoskeletal problems than Caucasian people (Bergman 2001, Allison 2002, Mc
Farlaine 2005). Also bad mood is 1,5x more prevalent in non-Western immigrants
in the Netherlands (www.statline.cbs.nl). Because bad mood and having physical
complaints are strongly correlated improvement of mood could be a cause as
well a result of improvement of aspecific musculoskeletal complaints.

We aim to assess the effect of high-dose vitamin D supplementation on
non-specific musculoskeletal complaints in non-Western vitamin D-deficient
immigrants and to determine whether improvement of mood is associated with this
effect.

Double blinded randomised controlled trial


Flow Diagram:

NW immigrants suffering > 3mnd non-spec
musculoskel. complaints, 25-OH-D <50nmol/L


Wk 0 Informed consent, Base-line metingen bij POH
+ Randomisation

200.000 IE vit D3 placebo

Wk 6 questionnaire questionnaire
200.000 IE vit D3 placebo



Wk 12 questionnaire questionnaire
evt 25-OH-D evt 25-OH-D

One group gets 200.000 IU vit D3 at week 0 and week 6
The other group get placebo at week 0 and week 6 and after de-blinding 200.000
IU vit D3 at week 12

About risk:
Adverse effects of 400.000 IU vitamin D3 administered in 6 weeks are almost
non-existent. Treatment of osteomalacia or rachitis is done with (in 6 weeks
cumulative ) doses of 2.000.000 IU. Studies showed that 25-OH-D levels less
than 500 nmol/L are harmless (R.Vieth 2006). Because every 400 IU/day raises
25-OH-D levels ca 10 nmol/L the dose used in this study can raise levels only
175 nmol/L. In my former trial, in which the same doses were used, nobody got
levels above the 125 nmol/L (Schreuder, 2012) The patient in this study
(included with levels < 50 nmol/L) will stay far under the 500 nmol/L level,
even when they dicide to use extra vitamin D themselves.
A supplementationtrial in the UK investigating supplementation with 200.000 IU
viutamin D in one gift showed no adverse effects (Daksha, 2003)
So, in case of sudden unexpected complaints first other causes should be
examined. If needed the given dose vitamin D can be known by contacting the
investigator; also a 25-OH-D level and calciumlevel can be easily determined.
Because vitamin D is a well-knwon drug that has been used for many years its
very unlikely new, unknown adverse effects wil be found.

About burden:
For diagnosis and treatment for non-specific musculoskeletal pain the GP will
advice a bloodproof anyhow. Beside the 25-OH-D the patient will get his
kreatinine investigated also for the sake of this study: a very small burden in
my opinion.
Patient will complete 4 times a questionnaire and will have an informed consent
procedure. This will take ca 75 min of his time; traveling and waiting times
comes extra.

About benifit:
Often bad mood or depression is underdiagnosed by GP's as well as by the
patients themselves. The nature of the questionnaires and the contact with the
POH-GGZ facilitates recognition and treatment of this mood-disorders (if they
exists)
Many supplemented patient are curious to know their 25-OH-D level after
supplementation. They will get the opportunity to know (if they want to)