Vitamin D in Fibromyalgia: A Causative or Confounding Biological Interplay?
Nutrients 2016, 8(6), 343; doi:10.3390/nu8060343
Spyridon Karras * , Eleni Rapti, Stauros Matsoukas and Kalliopi Kotsa
First Department of Internal Medicine, Division of Endocrinology and Metabolism, AHEPA Hospital, Thessaloniki 54636, Greece
FM suplementation with Vitamin D
Fibromyalgia (FM) is a chronic syndrome with an increasing prevalence, characterized by widespread musculoskeletal pain in combination with a variety of cognitive symptoms and fatigue. A plethora of scientific evidence that has accumulated during the last decades, resulted in a significant improvement of the understanding of the pathophysiology of the disease. However, current therapeutic approaches in patients with FM remains a multidimensional approach including patient education, behavioral therapy, exercise, pain management, and relief of chronic symptoms, rather than the use drug therapies, based on the mechanisms of disease development. Vitamin D, a fat-soluble vitamin derived mainly from skin synthesis through ultraviolet radiation, has been recognized to manifest a plethora of extraskeletal actions, apart from its fundamental role in skeletal and calcium homeostasis, including modulation of cell growth, neuromuscular actions, and potential anti-inflammatory properties. Recent findings indicate that hypovitaminosis D to be highly prevalent in patients with FM. Supplementation studies are limited so far, indicating potential beneficial effects on pain and severity of the disease, however specific recommendations are lacking. This review aims to summarize and critically appraise data regarding the pathophysiological interplay between vitamin D and FM, available results from observational and supplementation studies so far, with a clinical discourse on current knowledge gaps and future r
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Current criteria
Pain and symptoms over the past week, based on the total number of: painful areas out of 19 parts of the body
PLUS level of severity of these symptoms:
- a. Fatigue;
- b. Waking unrefreshed;
- c. Cognitive (memory or thought) problems
PLUS number of other general physical symptoms.
- Symptoms lasting at least three months at a similar level.
- No other health problem that would explain the pain and other symptoms
- Fibromyalgia is the second most common disorder observed by rheumatologists, after osteoarthritis)) [1-3].
Women are more likely to develop FM, since 85%-90% of the affected populations are females
Figure 1. Hypothetical pathophysiological mechanisms of vitamin D and FM interplay.
The presence of VDR receptors and the enzymatic action of 1-ahydroxylase in different areas of CNS and particularly in the hypothalamus, is implicated in the pathophysiology of FM and CWP
Vitamin D plays important role in neuronal regulation and modulates neurotransmitters and receptors like y-aminobutyric acid (GABA) and N-methyl-D-aspartate which correlates with FM
Vitamin D is involved in the production of Neural Growth Factor (NGF) which is implicated in the pathophysiology of FM
Neurotransmitters (acetylcholine, dopamine, serotonin) are associated with dysregulation of pain processing in FM
Inflammatory pathways associated with chronic pain like TGF-beta-1, interleukin-4 and nitric oxide (NO) are upregulated by vitamin D
Hypovitaminosis D results in myopathy of type II muscle fibers and fatty infiltration
Deep muscle hypersensitivity and balance deficit are associated with Vitamin D deficiency
Abbreviations: VDR: Vitamin D receptor; FM: Fibromyalgia; CNS: Central nervous system; CWP: Chronic widespread pain.
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- Wolfe, F.; Smythe, H.A.; Yunus, M.B.; Bennett, R.M.; Bombardier, C.; Goldenberg, D.L.; Tugwell, P.; Campbell, S.M.; Abeles, M.; Clark, P.; et al. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum. 1990, 33, 160-172. [CrossRef] [PubMed]
- Branco, J.C.; Bannwarth, B.; Failde, I.; Abello Carbonell, J.; Blotman, F.; Spaeth, M.; Saraiva, F.; Nacci, F.; Thomas, E.; Caubere, J.P.; et al. Prevalence of fibromyalgia: A survey in five European countries. Semin. Arthritis Rheum. 2010, 39, 448-453. [CrossRef] [PubMed]
- Bannwarth, B.; Blotman, F.; Lay, K.R.L.; Caubere, J.P.; Andre, E.; Taieb, C. Fibromyalgia syndrome in the general population of France: A prevalence study. ]t. Bone Spine 2009, 76,184-187. [CrossRef] [PubMed]
- Goldenberg, D.L.; Burckhardt, C.; Crofford, L. Management of fibromyalgia syndrome. JAMA 2004, 292, 2388-2395. [CrossRef] [PubMed]
- Picotto, G.; Liaudat, A.C.; Bohl, L.; Tolosa de Talamoni, N. Molecular aspects of vitamin D anticancer activity. Cancer Investig. 2012, 30, 604-614. [CrossRef] [PubMed]
- Christakos, S.; Dhawan, P.; Verstuyf, A.; Verlinden, L.; Carmeliet, G. Vitamin D: Metabolism, molecular mechanism of action, and pleiotropic effects. Physiol. Rev. 2016, 96, 365-408. [CrossRef] [PubMed]
- White, K.P.; Thompson, J. Fibromyalgia syndrome in an Amish community: A controlled study to determine disease and symptom prevalence. J. Rheumatol. 2003, 30,1835-1840. [PubMed]
- Jacobsen, S.; Prescott, E.; Kjoller, M.; Bulow, P.M.; Danneskiold-samsoe, B.; Kamper-jorgensen, F. Fibromyalgia in the adult Danish population: I. A prevalence study. Scand. J. Rheumatol. 1993, 22, 233-237.
- Topbas, M.; Cakirbay, H.; Gulec, H.; Akgol, E.; Ak, I.; Can, G. The prevalence of fibromyalgia in women aged 20-64 in Turkey. Scand. J. Rheum. 2005, 34,140-144. [PubMed]
- Makela, M.; Heliovaara, M. Prevalence of primary fibromyalgia in the Finish population. Br. Med. J. 1991, 303, 216-219. [CrossRef]
- Fitzcharles, M.A.; Boulos, P. Inaccuracy in the diagnosis of fibromyalgia syndrome: analysis of referrals. Rheumatology (Oxf.) 2003, 42, 263-267. [CrossRef]
- Wolfe, F.; Clauw, D.J.; Fitzcharles, M.A.; Goldenberg, D.L.; Katz, R.S.; Mease, P.; Russell, A.S.; Russell, I.J.; Winfield, J.B.; Yunus, M.B. The American College of Rheumatology Preliminary Diagnostic Criteria for Fibromyalgia and Measurement of Symptom Severity. Arthritis Care Res. 2010, 62, 600-610. [CrossRef] [PubMed]
- Wolfe, F.; Walitt, B.T.; Rasker, J.J.; Katz, R.S.; Hauser, W. The Use of Polysymptomatic Distress Categories in the Evaluation of Fibromyalgia (FM) and FM Severity. J. Rheumatol. 2015, 42, 1494-1501. [CrossRef] [PubMed]
- Wolfe, F.; Brahler, E.; Hinz, A.; Hauser, W. Fibromyalgia prevalence, somatic symptom reporting, and the dimensionality of polysymptomatic distress: Results from a survey of the general population. Arthritis Care Res. 2013, 65, 777-785. [CrossRef] [PubMed]
- Ferrari, R.; Russell, A.S. A questionnaire using the modified 2010 American College of Rheumatology Criteria for fibromyalgia: Specificity and sensitivity in clinical practice. J. Rheumatol. 2013, 40,1590-1595. [CrossRef] [PubMed]
- Russell, I.J.; Larson, A.A. Neurophysiopathogenesis of fibromyalgia syndrome: A unified hypothesis. Rheum Dis. Clin. N. Am. 2009, 35, 421-435. [CrossRef] [PubMed]
- Williams, D.A.; Clauw, D.J. Understanding fibromyalgia: Lessons from the broader pain research community. J. Pain 2009,10, 777-791. [CrossRef] [PubMed]
- Feng, J.; Zhang, Z.; Wu, X.; Mao, A.; Chang, F.; Deng, X.; Gao, H.; Ouyang, C.; Dery, K.J.; Le, K.; et al. Discovery of potential new gene variants and inflammatory cytokine associations with fibromyalgia syndrome by whole exome sequencing. PLoS ONE 2013, 8, e65033.
- Rodriguez-Revenga, L.; Madrigal, I.; Blanch-Rubio, J.; Elurbe, D.M.; Docampo, E.; Collado, A.; Vidal, J.; Carbonell, J.; Estivill, X.; Mila, M. Screening for the presence of FMR1 premutation alleles in women with fibromyalgia. Gene 2013, 512, 305-308. [CrossRef] [PubMed]
- Clauw, D.J.; Arnold, L.M.; McCarberg, B.H. The Science of Fibromyalgia. Mayo Clin. Proc. 2011, 86, 907-911. [CrossRef] [PubMed]
- Ablin, K.; Clauw, D.J. From fibrositis to functional somatic syndromes to a bell-shaped curve of pain and sensory sensitivity: Evolution of a clinical construct. Rheum. Dis. Clin. N. Am. 2009, 35, 233-251. [CrossRef] [PubMed]
- Marques, A.P.; Ferreira, E.A.; Matsutani, L.A.; Pereira, C.A.; Assumpgao, A. Quantifying pain threshold and quality of life of fibromyalgia patients. Clin. Rheumatol. 2005, 24, 266-271. [CrossRef] [PubMed]
- Gracely, R.H.; Petzke, F.; Wolf, J.M.; Clauw, D.J. Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthritis Rheum. 2002, 46,1333-1343. [CrossRef] [PubMed]
- McDermid, A.J.; Rollman, G.B.; McCain, G.A. Generalized hypervigilance in fibromyalgia: Evidence of perceptual amplification. Pain 1996, 66,133-144. [CrossRef]
- Russell, I.J.; Vaeroy, H.; Javors, M.; Nyberg, F. Cerebrospinal fluid biogenic amine metabolites in fibromyalgia/fibrositis syndrome and rheumatoid arthritis. Arthritis Rheum. 1992, 35, 550-556. [CrossRef] [PubMed]
- Baraniuk, J.N.; Whalen, G.; Cunningham, J.; Clauw, D.J. Cerebrospinal fluid levels of opioid peptides in fibromyalgia and chronic low back pain. BMC Musculoskelet. Disord. 2004, 5, 48. [CrossRef] [PubMed]
- Harris, R.E.; Clauw, D.J.; Scott, D.J.; McLean, S.A.; Gracely, R.H.; Zubieta, J.K. Decreased central mu-opioid receptor availability in fibromyalgia. J. Neurosci. 2007,27,10000-10006. [CrossRef] [PubMed]
- Arnold, L.M. The pathophysiology, diagnosis, and treatment of fibromyalgia. Psychiatr. Clin. N. Am. 2010, 33, 375-408. [CrossRef] [PubMed]
- May, A. Chronic pain may change the structure of the brain. Pain 2008,137, 7-15. [CrossRef] [PubMed]
- DeLeo, J.A.; Yezierski, R.P. The role of neuroinflammation and neuroimmune activation in persistent pain. Pain 2001, 90,1-6. [CrossRef]
- Bosma, R.L.; Mojarad, E.A.; Leung, L.; Pukall, C.; Staud, R.; Stroman, P.W. FMRI of spinal and supra-spinal correlates of temporal pain summation in fibromyalgia patients. Hum. Brain Map. 2016. in press.
- Carrillo-de-la-Pena, M.T.; Vallet, M.; Perez, M.I.; Gomez-Perretta, C. Intensity dependence of auditory-evoked cortical potentials in fibromyalgia patients: A test of the generalized hypervigilance hypothesis. J. Pain 2006, 7, 480-487. [CrossRef] [PubMed]
- Cazzola, M.; Atzeni, F.; Boccassini, L.; Cassisi, G.; Sarzi-Puttini, P. Physiopathology of pain in rheumatology. Reumatismology 2014, 66, 4-13. [CrossRef] [PubMed]
- Kalueff, A.V.; Tuohimaa, P. Neurosteroid hormone vitamin D and its utility in clinical nutrition. Curr. Opin. Clin. Nutr. Metab. Care 2007,10,12-19. [CrossRef] [PubMed]
- Holick, M.F.; Chen, T.C. Vitamin D deficiency: A worldwide problem health consequences. Am. J. Clin. Nutr. 2008, 87,1080S-1086S. [CrossRef] [PubMed]
- Holick, M.F. Vitamin D deficiency. N. Engl. J. Med. 2007, 357, 266-281. [CrossRef] [PubMed]
- Shipton, E.A.; Shipton, E.E. Vitamin D and Pain: Vitamin D and Its Role in the Aetiology and Maintenance of Chronic Pain States and Associated Comorbidities. Pain Res. Treat. 2015, 2015, 904967. [CrossRef] [PubMed]
- Jirikowski, G.F.; Kauntzer, U.W.; Dief, A.E.E.; Caldwell, J.D. Distribution of vitamin D binding protein expressing neurons in the rat hypothalamus. Histochem. Cell Biol. 2009,131, 365-370. [CrossRef] [PubMed]
- Plotnikoff, G.A.; Quigley, J.M. Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific musculoskeletal pain. Mayo Clin. Proc. 2003, 78,1463-1470. [CrossRef] [PubMed]
- Eyles, D.W.; Smith, S.; Kinobe, R.; Hewison, M.; McGrath, J.J. Distribution of the Vitamin D receptor and 1-alpha-hydroxylase in human brain. J. Chem. Neuroanat. 2005, 29, 21-30. [CrossRef] [PubMed]
- Mensah-Nyagan, A.G.; Meyer, L.; Schaeffer, V.; Kibaly, C.; Patte-Mensah, C. Evidence for a key role of steroids in the modulation of pain. Psychoneuroendocrinology 2009, 34, S169-S177. [CrossRef] [PubMed]
- Russell, I.J.; Holman, A.J.; Swick, T.J.; Alvarez-Horine, S.; Wang, Y.G.; Guinta, D.; Sodium Oxybate 06-008 FM Study Group. Sodium oxybate reduces pain, fatigue, and sleep disturbance and improves functionality in fibromyalgia: Results from a 14-week, randomized, double-blind, placebo-controlled study. Pain 2011, 152,1007-1017. [CrossRef] [PubMed]
- Neveu, I.; Naveilhan, P.; Jehan, F.; Baudet, C.; Wion, D.; De Luca, H.F.; Brachet, P. 1,25-dihydroxyvitamin D3 regulates the synthesis of nerve growth factor in primary cultures of glial cells. Brain Res. Mol. Brain Res. 1994, 24, 70-76. [CrossRef]
- Sanchez, B.; Relova, J.L.; Gallego, R.; Ben-Batalla, I.; Perez-Fernandez, R. 1,25-Dihydroxyvitamin D3 administration to 6-hydroxydopamine-lesioned rats increases glial cell line-derived neurotrophic factor and partially restores tyrosine hydroxylase expression in substantia nigra and striatum. J. Neurosci. Res. 2009, 87, 723-732. [CrossRef] [PubMed]
- Sarchielli, P.; Alberti, A.; Candeliere, A.; Floridi, A.; Capocchi, G.; Calabresi, P. Glial cell line-derived neurotrophic factor and somatostatin levels in cerebrospinal fluid of patients affected by chronic migraine and fibromyalgia. Cephalalgia 2006, 26, 409-415. [CrossRef] [PubMed]
- Albrecht, D.S.; MacKie, P.J.; Kareken, D.A.; Hutchins, G.D.; Chumin, E.J.; Christian, B.T.; Yoder, K.K. Differential dopamine function in fibromyalgia. Brain Imaging Behav. 2015. [CrossRef] [PubMed]
- Garcion, E.; Wion-Barbot, N.; Montero-Menei, C.N.; Berger, F.; Wion, D. New clues about vitamin D functions in the nervous system. Trends Endocrinol. Metab. 2002,13,100-105. [CrossRef]
- Leung, L.; Cahill, C.M. TNF-a and neuropathic pain—A review. J. Neuroinflamm. 2010. [CrossRef] [PubMed]
- Liu, D.; Fernandez, B.O.; Hamilton, A.; Lang, N.N.; Gallagher, J.M.; Newby, D.E.; Feelisch, M.; Weller, R.B. UVA irradiation of human skin vasodilates arterial vasculature and lowers blood pressure independently of nitric oxide synthase. J. Investig. Dermatol. 2014,134,1839-1846. [CrossRef] [PubMed]
- Oplander, C.; Volkmar, C.M.; Paunel-Gorgulu, A.; van Faassen, E.E.; Heiss, C.; Kelm, M.; Halmer, D.; Murtz, M.; Pallua, N.; Suschek, C.V. Whole body UVA irradiation lowers systemic blood pressure by release of nitric oxide from intracutaneous photolabile nitric oxide derivates. Circ. Res. 2009, 105, 1031-1040. [CrossRef] [PubMed]
- Boland, R. Role of Vitamin D in skeletal muscle function. Endocr. Rev. 1986, 7, 434-447. [CrossRef] [PubMed]
- Von Kanel, R.; Muller-Hartmannsgruber, V.; Kokinogenis, G.; Egloff, N. Vitamin D and central hypersensitivity in patients with chronic pain. Pain Med. 2014,15,1609-1618. [CrossRef] [PubMed]
- Olama, S.M.; Senna, M.K.; Elarman, M.M.; Elhawary, G. Serum vitamin D level and bone mineral density in premenopausal Egyptian women with fibromyalgia. Rheumatol. Int. 2013, 33,185-192. [CrossRef] [PubMed]
- Mateos, F.; Valero, C.; Olmos, J.M.; Casanueva, B.; Castillo, J.; Martinez, J.; Hernandez, J.L.; Gonzalez Macias, J. Bone mass and vitamin D levels in women with a diagnosis of fibromyalgia. Osteoporos. Int. 2014, 25, 525-533. [CrossRef] [PubMed]
- Tague, S.E.; Clarke, G.L.; Winter, M.K.; McCarson, K.E.; Wright, D.E.; Smith, P.G. Vitamin D deficiency promotes skeletal muscle hypersensitivity and sensory hyperinnervation. J. Neurosci. 2011, 31,13728-13738. [CrossRef] [PubMed]
- Jesus, C.A.; Feder, D.; Peres, M.F. The role of vitamin D in pathophysiology and treatment of fibromyalgia. Curr. Pain Headache Rep. 2013,17, 355. [CrossRef] [PubMed]
- Karvelas, D.; Vasudevan, S.V. Fibromyalgia syndrome. Pain Manag. 2011,1, 557-570. [CrossRef] [PubMed]
- Huisman, A.M.; White, K.P.; Algra, A.; Harth, M.; Vieth, R.; Jacobs, J.W.; Bijlsma, J.W.; Bell, D.A. Vitamin D levels in women with systemic lupus erythematosus and fibromyalgia. J. Rheumatol. 2001, 28, 2535-2539. [PubMed]
- Bhatty, S.A.; Shaikh, N.A.; Irfan, M.; Kashif, S.M.; Vaswani, A.S.; Sumbhai, A.; Gunpat, J. Vitamin D deficiency in fibromyalgia. JPMA 2010, 60, 949-951.
- McCabe, P.S.; Pye, S.R.; Beth, J.M.; Lee, D.M.; Tajar, A.; Bartfai, G.; Boonen, S.; Bouillon, R.; Casanueva, F.; Finn, J.D.; et al. Low vitamin D and the risk of developing chronic widespread pain: Results from the European male ageing study. BMC Musculoskelet. Disord. 2016,17, 32. [CrossRef] [PubMed]
- Tandeter, H.; Grynbaum, M.; Zuili, I.; Shany, S.; Shvartzman, P. Serum 25-OH vitamin D levels in patients with fibromyalgia. Israel Med. Assoc J. 2009,11, 339-342.
- Armstrong, D.J.; Meenagh, G.K.; Bickle, I.; Lee, A.S.; Curran, E.S.; Finch, M.B. Vitamin D deficiency is assiciated with anxiety and depression in fibromyalgia. Clin. Rheumatol. 2007, 26, 551-554. [CrossRef] [PubMed]
- De Rezende Pena, C.; Grillo, L.P.; Das Chagas Medeiros, M.M. Evaluation of 25-hydroxyvitamin D serum levels in patients with fibromyalgia. J. Clin. Rheumatol. 2010,16, 365-369. [CrossRef] [PubMed]
- Karras, S.N.; Anagnostis, P.; Paschou, S.A.; Kandaraki, E.; Goulis, D.G. Vitamin D status during pregnancy: Time for a more unified approach beyond borders? Eur. J. Clin. Nutr. 2015, 69, 874-877. [CrossRef] [PubMed]
- Anagnostis, P.; Karras, S.N.; Athyros, V.G.; Annweiler, C.; Karagiannis, A. The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes. Lancet Diabetes Endocrinol. 2014, 2, 362-363. [CrossRef]
- Hsiao, M.Y.; Hung, C.Y.; Chang, K.V.; Han, D.S.; Wang, T.G. Is serum hypovitaminosis D associated with chronic widespread pain including fibromyalgia? A meta-analysis of observational studies. Pain Phys. 2015, 18, E877-E887.
- Badsha, H.; Daher, M.; Ooi Kong, K. Myalgias or non-specific muscle pain in Arab or Indo-Pakistani patients may indicate vitamin D deficiency. Clin. Rheumatol. 2009,28, 971-973. [CrossRef] [PubMed]
- Harari, M.; Dramsdahl, E.; Shany, S.; Baumfeld, Y.; Ingber, A.; Novack, V.; Sukenik, S. Increased vitamin D serum levels correlate with clinical improvement of rheumatic diseases after Dead Sea climatotherapy. Israel Med. Assoc. J. 2011,13, 212-215.
- Matthana, M.H. The relation between vitamin D deficiency and fibromyalgia syndrome in women. Saudi Med. J. 2011,32,925-929. [PubMed]
- Abokrysha, N.T. Vitamin D deficiency in women with fibromyalgia in Saudi Arabia. Pain Med. 2012, 13, 452-458. [CrossRef] [PubMed]
- Warner, A.E.; Arnspiger, S.A. Diffuse musculoskeletal pain is not associated with low vitamin D levels or improved by treatment with vitamin D. J. Clin. Rheumatol. 2008,14,12-16. [CrossRef] [PubMed]
- Wepner, F.; Scheuer, R.; Schuetz-Wieser, B.; Machacek, P.; Pieler-Bruha, E.; Cross, H.S.; Hahne, J.; Friedrich, M. Effects of vitamin D on patients with fibromyalgia syndrome: A randomized placebo-controlled trial. Pain 2014,155,261-268. [CrossRef] [PubMed]
- Tripkovic, L.; Lambert, H.; Hart, K.; Smith, C.P.; Bucca, G.; Penson, S.; Chope, G.; Hypponen, E.; Berry, J.; Vieth, R.; et al. Comparison of vitamin D2 and vitamin D3 supplementation in raising serum 25-hydroxyvitamin D status: A systematic review and meta-analysis. Am. J. Clin. Nutr. 2012, 95,1357-1364. [CrossRef] [PubMed]
- Autier, P.; Gandini, S.; Mullie, P. A systematic review: Influence of vitamin D supplementation on serum 25-hydroxyvitamin D concentration. J. Clin. Endocrinol. Metab. 2012, 97,2606-2613. [CrossRef] [PubMed]
- Chowdhury, R.; Kunutsor, S.; Vitezova, A.; Oliver-Williams, C.; Chowdhury, S.; Kiefte-de-Jong, J.C.; Khan, H.; Baena, C.P.; Prabhakaran, D.; Hoshen, M.B.; et al. Vitamin D and risk of cause specific death: Systematic review and meta-analysis of observational cohort and randomised intervention studies. BMJ 2014, 348, g1903. [CrossRef] [PubMed]
- Heaney, R.P. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr. Rev. 2014, 72,48-54. [CrossRef] [PubMed]
- Karras, S.N.; Anagnostis, P.; Naughton, D.; Annweiler, C.; Petroczi, A.; Goulis, D.G. Vitamin D during pregnancy: Why observational studies suggest deficiency and interventional studies show no improvement in clinical outcomes? A narrative review. J. Endocrinol. Invest. 2015, 38,1265-1275. [CrossRef] [PubMed]
See in VitaminDWiki Pregnancies - Vitamin D intervention benefits not seen for 6 reasons– July 2015 - Vieth, R.; Chan, P.C.; MacFarlane, G.D. Efficacy and safety of vitamin D3 intake exceeding the lowest observed adverse effect level. Am. J. Clin. Nutr. 2001, 73, 288-294. [PubMed]
- Karras, S.N.; Anagnostis, P.; Annweiler, C.; Naughton, D.P.; Petroczi, A.; Bili, E.; Harizopoulou, V.; Tarlatzis, B.C.; Persinaki, A.; Papadopoulou, F.; et al. Maternal vitamin D status during pregnancy: The Mediterranean reality. Eur. J. Clin. Nutr. 2014, 68, 864-869. [CrossRef] [PubMed]
- Van der Meer, I.M.; Middelkoop, B.J.; Boeke, A.J.; Lips, P. Prevalence of vitamin D deficiency among Turkish, Moroccan, Indian and sub-Sahara African populations in Europe and their countries of origin: An overview. Osteoporos. Int. 2011, 22,1009-1021. [CrossRef] [PubMed]