Vitamin D deficiency

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In medicine, vitamin D deficiency is "a nutritional condition produced by a deficiency of vitamin D in the diet, insufficient production of vitamin D in the skin, inadequate absorption of vitamin D from the diet, or abnormal conversion of vitamin D to its bioactive metabolites. It is manifested clinically as rickets in children and osteomalacia in adults."[1]

Definition

Health science has reached no consensus on what constitutes optimal and suboptimal vitamin D status, evaluated by blood plasma concentration of 25-hydroxyvitamin D, currently the best status indicator.

Recommended serum levels are 20 ng/mL (50 nmol/L) according to the Institute of Medicine (IOM)[2] and 30 ng/mL (75 nmol/L) according to the International Osteoporosis Foundation[3], Osteoporosis Canada[4], and Endocrine Society[5].

Institute of Medicine states (page 13):

  • Levels over 20 ng/ml: "Practically all persons are sufficient"
  • Levels 12-20 ng/ml: "Some, but not all, persons are potentially at risk for inadequacy."
  • Levels below 12 ng/ml: "persons are at risk of deficiency."

The IOM based their recommendations in part on a prior systematic review by the Agency for Healthcare Research and Quality.[6]

A more recent cohort study agrees that levels about 20 ng/ml are desirable.[7]

Vitamin D and bone density

It is unclear is vitamin D supplementation increased bone density according to a meta-analysis of randomized controlled trials..[8]

Vitamin D levels and prevention of fractures

Reviews conflict on this topic.[9][10][11][12]

One review concluded that "mean serum 25(OH)D levels of about 75 to 110 nmol/l provide optimal benefits for all investigated endpoints without increasing health risks."[9]

Epidemiology and prevalence

About a quarter of older adults have levels below 20 ng/mL.[13]

Low levels of vitamin D are common in medical inpatients.[14]

Levels below 47.5 nmol/L are associated with increased risk of hip fracture in women.[15] Low levels are associated (below 20 nmol/L and maybe below 63 nmol/L) with increased fracture risk in men.[16]

Risk factors

Vitamind D levels are related to 'total vitamin D intake from foods and supplements, waist circumference, recreational physical activity, race-ethnicity, regional solar irradiance, and age."[17]

"The FokI, BsmI, ApaI, and TaqI VDR polymorphisms are not associated with BMD or with fractures, but the Cdx2 polymorphism may be associated with risk for vertebral fractures" according to an observational study.[18] However, TaqI and FokI polymorphisms of the vitamin D receptor may be important to treatment of Mycobacterium tuberculosis.[19]

Diagnosis

Symptoms

Vitamin D was reported to be associated with widespread musculoskeletal pain like fibromyalgia[20].[21] However, this was an uncontrolled study and more recent studies make the associated between Vitamin D and non-specific pain doubtful[22] and suggest that earlier recommendations[20] to screen patients with musculoskeletal pain for deficiency of vitamin D may not be justified.

Laboratory test

The serum level of 25-hydroxyvitamin D is the best metabolize to assay.[23][24] Assay method influences the result.[25]

Treatment

Clinical practice guidelines direct treatment.[5] Treatment of adults can be either 50,000 IU of D2 or D3 once a week for eight weeks or 6,000 IU daily. This is followed by 1,500 to 2,000 IU per day. Some populations may require higher doses.

A more recent randomized controlled trial showed that, among white women with vitamin D insufficiency and deficiency (levels 13 to 50 nmol/L;5 to 20 ng/mL ), a dose of 600 to 800 IU per day of vitamin D3 will raise the level above Institute of Medicine recommendations (20 ng/mL or 50 nmol/L) in 97% of women.[26] D3 may be more effective than D2.[27]

Obese patients need more vitamin D to raise their level.[28]

Does higher than at least 800 IU daily may be best for prevention of fractures.[29]

Drug toxicity

Daily intake of 1000 mg of elemental calcium as calcium carbonate with 400 IU of vitamin D3 may increase urolithiasis according to the Women's Health Initiative randomized controlled trial.[30][31] This trial has been criticized because average age of the women at enrollment was 62 and they were only followed for 7 years; both problem may obscure benefit on fracture prevention.[32]


Absolute rates of outcomes[30]
&nbsp Vitamin D plus calcium
(18,176 patients)
Placebo
(18,106 patients)
Absolute difference Number needed[32]
Hip fractures 175 199 24 less in supplementation group 1986 to treat*
Urolithiasis 449 381 68 more in supplementation group 284 to harm
* Among compliant patients. There was no significant benefit among all patients (absolute rate difference of 0.02 would indicate a number needed to treat of 5000 if the value were significant in a larger study).

Although vitamin D supplementation has been suggested to increase cardiovascular mortality[33], this conclusion has been disputed.[34]

Screening

Clinical practice guidelines suggest screening of special populations with the 25-hydroxyvitamin D [25(OH)D] assay.[5]

References

  1. Anonymous (2015), Vitamin D deficiency (English). Medical Subject Headings. U.S. National Library of Medicine.
  2. Committee to Review Dietary References Intakes for Vitamin D and Calcium. Ross AC et al., editors. (2010) Dietary References Intakes for Calcium and Vitamin D. Institute of Medicine.
  3. Dawson-Hughes B, Mithal A, Bonjour JP, Boonen S, Burckhardt P, Fuleihan GE et al. (2010). "IOF position statement: vitamin D recommendations for older adults.". Osteoporos Int 21 (7): 1151-4. DOI:10.1007/s00198-010-1285-3. PMID 20422154. Research Blogging.
  4. Hanley DA, Cranney A, Jones G, Whiting SJ, Leslie WD, Guidelines Committee of the Scientific Advisory Council of Osteoporosis Canada (2010). "Vitamin D in adult health and disease: a review and guideline statement from Osteoporosis Canada (summary).". CMAJ 182 (12): 1315-9. DOI:10.1503/cmaj.091062. PMID 20624865. PMC PMC2934797. Research Blogging.
  5. 5.0 5.1 5.2 Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP et al. (2011). "Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline.". J Clin Endocrinol Metab 96 (7): 1911-30. DOI:10.1210/jc.2011-0385. PMID 21646368. Research Blogging.
  6. Chung M, Balk EM, Brendel M, Ip S, Lau J, Lee J et al. (2009). "Vitamin D and calcium: a systematic review of health outcomes.". Evid Rep Technol Assess (Full Rep) (183): 1-420. PMID 20629479[e]
  7. de Boer IH, Levin G, Robinson-Cohen C, Biggs ML, Hoofnagle AN, Siscovick DS et al. (2012). "Serum 25-hydroxyvitamin D concentration and risk for major clinical disease events in a community-based population of older adults: a cohort study.". Ann Intern Med 156 (9): 627-34. DOI:10.1059/0003-4819-156-9-201205010-00004. PMID 22547472. Research Blogging.
  8. Reid, Ian R; Mark J Bolland, Andrew Grey (2013-10). "Effects of vitamin D supplements on bone mineral density: a systematic review and meta-analysis". The Lancet. DOI:10.1016/S0140-6736(13)61647-5. ISSN 01406736. Retrieved on 2013-10-11. Research Blogging.
  9. 9.0 9.1 Bischoff-Ferrari HA, Shao A, Dawson-Hughes B, Hathcock J, Giovannucci E, Willett WC (2010). "Benefit-risk assessment of vitamin D supplementation.". Osteoporos Int 21 (7): 1121-32. DOI:10.1007/s00198-009-1119-3. PMID 19957164. PMC PMC3062161. Research Blogging.
  10. DIPART (Vitamin D Individual Patient Analysis of Randomized Trials) Group (2010). "Patient level pooled analysis of 68 500 patients from seven major vitamin D fracture trials in US and Europe.". BMJ 340: b5463. DOI:10.1136/bmj.b5463. PMID 20068257. PMC PMC2806633. Research Blogging.
  11. Bischoff-Ferrari HA, Willett WC, Wong JB, Stuck AE, Staehelin HB, Orav EJ et al. (2009). "Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials.". Arch Intern Med 169 (6): 551-61. DOI:10.1001/archinternmed.2008.600. PMID 19307517. Research Blogging. Review in: Ann Intern Med. 2009 Aug 18;151(4):JC2-8 Review in: Evid Based Med. 2009 Oct;14(5):149
  12. Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T, Dawson-Hughes B (2005). "Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials.". JAMA 293 (18): 2257-64. DOI:10.1001/jama.293.18.2257. PMID 15886381. Research Blogging. Review in: ACP J Club. 2005 Nov-Dec;143(3):72-4
  13. Orwoll E, Nielson CM, Marshall LM, et al (April 2009). "Vitamin D deficiency in older men". J. Clin. Endocrinol. Metab. 94 (4): 1214–22. DOI:10.1210/jc.2008-1784. PMID 19174492. Research Blogging.
  14. Thomas MK, Lloyd-Jones DM, Thadhani RI, et al (1998). "Hypovitaminosis D in medical inpatients". N. Engl. J. Med. 338 (12): 777–83. PMID 9504937[e]
  15. Cauley JA, Lacroix AZ, Wu L, Horwitz M, Danielson ME, Bauer DC et al. (2008). "Serum 25-hydroxyvitamin D concentrations and risk for hip fractures.". Ann Intern Med 149 (4): 242-50. PMID 18711154. PMC PMC2743412[e]
  16. Cauley JA, Parimi N, Ensrud KE, Bauer DC, Cawthon PM, Cummings SR et al. (2010). "Serum 25-hydroxyvitamin D and the risk of hip and nonspine fractures in older men.". J Bone Miner Res 25 (3): 545-53. DOI:10.1359/jbmr.090826. PMID 19775201. PMC PMC3121172. Research Blogging.
  17. Millen AE, Wactawski-Wende J, Pettinger M, Melamed ML, Tylavsky FA, Liu S et al. (2010). "Predictors of serum 25-hydroxyvitamin D concentrations among postmenopausal women: the Women's Health Initiative Calcium plus Vitamin D clinical trial.". Am J Clin Nutr 91 (5): 1324-35. DOI:10.3945/ajcn.2009.28908. PMID 20219959. PMC PMC2854906. Research Blogging.
  18. Uitterlinden AG, Ralston SH, Brandi ML, Carey AH, Grinberg D, Langdahl BL et al. (2006). "The association between common vitamin D receptor gene variations and osteoporosis: a participant-level meta-analysis.". Ann Intern Med 145 (4): 255-64. PMID 16908916[e]
  19. Martineau AR, Timms PM, Bothamley GH, Hanifa Y, Islam K, Claxton AP et al. (2011). "High-dose vitamin D(3) during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial.". Lancet 377 (9761): 242-50. DOI:10.1016/S0140-6736(10)61889-2. PMID 21215445. Research Blogging.
  20. 20.0 20.1 Plotnikoff GA, Quigley JM (2003). "Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific musculoskeletal pain". Mayo Clin. Proc. 78 (12): 1463–70. PMID 14661675[e]
  21. Hicks GE, Shardell M, Miller RR, et al (May 2008). "Associations between vitamin D status and pain in older adults: the Invecchiare in Chianti study". J Am Geriatr Soc 56 (5): 785–91. DOI:10.1111/j.1532-5415.2008.01644.x. PMID 18331295. Research Blogging.
  22. Warner AE, Arnspiger SA (February 2008). "Diffuse musculoskeletal pain is not associated with low vitamin D levels or improved by treatment with vitamin D". J Clin Rheumatol 14 (1): 12–6. DOI:10.1097/RHU.0b013e31816356a9. PMID 18431091. Research Blogging.
  23. Rosen, Clifford J. (2011-01-20). "Vitamin D Insufficiency". New England Journal of Medicine 364 (3): 248-254. DOI:10.1056/NEJMcp1009570. ISSN 0028-4793. Research Blogging.
  24. Pearce SH, Cheetham TD (2010). "Diagnosis and management of vitamin D deficiency.". BMJ 340: b5664. DOI:10.1136/bmj.b5664. PMID 20064851. Research Blogging.
  25. Barake M, Daher RT, Salti I, Cortas NK, Al-Shaar L, Habib RH et al. (2012). "25-hydroxyvitamin d assay variations and impact on clinical decision making.". J Clin Endocrinol Metab 97 (3): 835-43. DOI:10.1210/jc.2011-2584. PMID 22238386. Research Blogging.
  26. Gallagher JC, Sai A, Templin T, Smith L (2012). "Dose response to vitamin d supplementation in postmenopausal women: a randomized trial.". Ann Intern Med 156 (6): 425-37. DOI:10.1059/0003-4819-156-6-201203200-00005. PMID 22431675. Research Blogging.
  27. Lehmann U, Hirche F, Stangl GI, Hinz K, Westphal S, Dierkes J (2013). "Bioavailability of vitamin D(2) and D(3) in healthy volunteers, a randomized placebo-controlled trial.". J Clin Endocrinol Metab 98 (11): 4339-45. DOI:10.1210/jc.2012-4287. PMID 24001747. Research Blogging.
  28. Drincic A, Fuller E, Heaney RP, Armas LA (2013). "25-hydroxyvitamin D response to graded vitamin D3 supplementation among obese adults.". J Clin Endocrinol Metab 98 (12): 4845-51. DOI:10.1210/jc.2012-4103. PMID 24037880. Research Blogging.
  29. Bischoff-Ferrari HA, Willett WC, Orav EJ, Lips P, Meunier PJ, Lyons RA et al. (2012). "A pooled analysis of vitamin D dose requirements for fracture prevention.". N Engl J Med 367 (1): 40-9. DOI:10.1056/NEJMoa1109617. PMID 22762317. Research Blogging.
  30. 30.0 30.1 Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE et al. (2006). "Calcium plus vitamin D supplementation and the risk of fractures.". N Engl J Med 354 (7): 669-83. DOI:10.1056/NEJMoa055218. PMID 16481635. Research Blogging. Review in: ACP J Club. 2006 Jul-Aug;145(1):4-5 Review in: Evid Based Nurs. 2006 Oct;9(4):114
  31. Wallace RB, Wactawski-Wende J, O'Sullivan MJ, Larson JC, Cochrane B, Gass M et al. (2011). "Urinary tract stone occurrence in the Women's Health Initiative (WHI) randomized clinical trial of calcium and vitamin D supplements.". Am J Clin Nutr 94 (1): 270-7. DOI:10.3945/ajcn.110.003350. PMID 21525191. PMC PMC3127502. Research Blogging.
  32. 32.0 32.1 Fletcher RH (2006). "Calcium plus vitamin D did not prevent hip fracture or colorectal cancer in postmenopausal women.". ACP J Club 145 (1): 4-5. PMID 16813354[e]
  33. Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR (2011). "Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women's Health Initiative limited access dataset and meta-analysis.". BMJ 342: d2040. DOI:10.1136/bmj.d2040. PMID 21505219. PMC PMC3079822. Research Blogging. Review in: Ann Intern Med. 2011 Aug 16;155(4):JC2-3 Review in: Evid Based Med. 2012 Feb;17(1):16-7
  34. Crandall CJ, Cauley JA (2011). "ACP Journal Club. Calcium plus vitamin D was associated with increased cardiovascular risk in women not taking personal calcium supplements.". Ann Intern Med 155 (4): JC2-3. DOI:10.1059/0003-4819-155-4-201108160-02003. PMID 21844536. Research Blogging.