Screening for Vitamin D Deficiency in Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force | Complementary and Alternative Medicine | JAMA | JAMA Network
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Figure 1.  Analytic Framework: Screening for Vitamin D Deficiency in Adults
Analytic Framework: Screening for Vitamin D Deficiency in Adults
Figure 2.  Literature Search Flow Diagram: Screening for Vitamin D Deficiency in Adults
Literature Search Flow Diagram: Screening for Vitamin D Deficiency in Adults

KQ indicates key question.

Figure 3.  Effect of Vitamin D Treatment on Mortality Stratified by Setting
Effect of Vitamin D Treatment on Mortality Stratified by Setting

Size of each data marker indicates the weight of the study in the analysis. Weights are from random-effects analysis. To calculate the absolute risk difference in percentage points, multiply value by 100 (eg, 0.009 multiplied by 100 = 0.9 percentage points).

Figure 4.  Effect of Vitamin D Treatment on Incidence of Any Fracture in Community-Dwelling Participants
Effect of Vitamin D Treatment on Incidence of Any Fracture in Community-Dwelling Participants

Size of each data marker indicates the weight of the study in the analysis. Weights are from random-effects analysis. To calculate the absolute risk difference in percentage points, multiply value by 100 (eg, 0.009 multiplied by 100 = 0.9 percentage points).

Figure 5.  Effects of Vitamin D Treatment on Incidence of Falls in Community-Dwelling Participants
Effects of Vitamin D Treatment on Incidence of Falls in Community-Dwelling Participants

Size of each data marker indicates the weight of the study in the analysis. Weights are from random-effects analysis. To calculate the absolute risk difference in percentage points, multiply value by 100 (eg, 0.009 multiplied by 100 = 0.9 percentage points).

Figure 6.  Effect of Vitamin D Treatment on Total Number of Falls in Community-Dwelling Participants
Effect of Vitamin D Treatment on Total Number of Falls in Community-Dwelling Participants

Size of each data marker indicates the weight of the study in the analysis. Weights are from random-effects analysis. To calculate the RD in percentage points, multiply value by 100 (eg, 0.009 multiplied by 100 = 0.9 percentage points).

Table 1.  Study Characteristics of RCTs Reporting Benefits and Harms of Treating Low Serum Vitamin D Levels in Adults
Study Characteristics of RCTs Reporting Benefits and Harms of Treating Low Serum Vitamin D Levels in Adults
Table 2.  Summary of Evidence for Screening for Vitamin D Deficiency in Adults
Summary of Evidence for Screening for Vitamin D Deficiency in Adults
1.
Institute of Medicine.  Dietary Reference Intakes For Calcium and Vitamin D. National Academies Press; 2011.
2.
Pludowski  P, Holick  MF, Pilz  S,  et al.  Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality—a review of recent evidence.   Autoimmun Rev. 2013;12(10):976-989. doi:10.1016/j.autrev.2013.02.004PubMedGoogle ScholarCrossref
3.
Autier  P, Mullie  P, Macacu  A,  et al.  Effect of vitamin D supplementation on non-skeletal disorders: a systematic review of meta-analyses and randomised trials.   Lancet Diabetes Endocrinol. 2017;5(12):986-1004. doi:10.1016/S2213-8587(17)30357-1PubMedGoogle ScholarCrossref
4.
Sempos  CT, Heijboer  AC, Bikle  DD,  et al.  Vitamin D assays and the definition of hypovitaminosis D: results from the First International Conference on Controversies in Vitamin D.   Br J Clin Pharmacol. 2018;84(10):2194-2207. doi:10.1111/bcp.13652PubMedGoogle ScholarCrossref
5.
Ross  AC, Manson  JE, Abrams  SA,  et al.  The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know.   J Clin Endocrinol Metab. 2011;96(1):53-58. doi:10.1210/jc.2010-2704PubMedGoogle ScholarCrossref
6.
Holick  MF, Binkley  NC, Bischoff-Ferrari  HA,  et al; Endocrine Society.  Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline.   J Clin Endocrinol Metab. 2011;96(7):1911-1930. doi:10.1210/jc.2011-0385PubMedGoogle ScholarCrossref
7.
LeFevre  ML; US Preventive Services Task Force.  Screening for vitamin D deficiency in adults: U.S. Preventive Services Task Force recommendation statement.   Ann Intern Med. 2015;162(2):133-140. doi:10.7326/M14-2450PubMedGoogle ScholarCrossref
8.
LeBlanc  E, Chou  R, Zakher  B, Daeges  M, Pappas  M.  Screening for Vitamin D deficiency: Systematic Review for the U.S. Preventive Services Task Force Recommendation. US Preventive Services Task Force; 2014.
9.
LeBlanc  ES, Zakher  B, Daeges  M, Pappas  M, Chou  R.  Screening for vitamin D deficiency: a systematic review for the U.S. Preventive Services Task Force.   Ann Intern Med. 2015;162(2):109-122. doi:10.7326/M14-1659PubMedGoogle ScholarCrossref
10.
Kahwati  LC, LeBlanc  E, Weber  RP,  et al.  Screening for Vitamin D Deficiency in Adults: An Evidence Review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 201. Agency for Healthcare Research and Quality; 2021. AHRQ publication 20-05270-EF-1.
11.
 Human Development Report 2016. United Nations Development Programme; 2016.
12.
Sterne  JAC, Savović  J, Page  MJ,  et al.  RoB 2: a revised tool for assessing risk of bias in randomised trials.   BMJ. 2019;366:l4898. doi:10.1136/bmj.l4898PubMedGoogle ScholarCrossref
13.
DerSimonian  R, Laird  N.  Meta-analysis in clinical trials.   Control Clin Trials. 1986;7(3):177-188. doi:10.1016/0197-2456(86)90046-2PubMedGoogle ScholarCrossref
14.
Agency for Healthcare Research and Quality.  Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Agency for Healthcare Research and Quality; 2014. AHRQ publication 10(14)-EHC063-EF.
15.
Arvold  DS, Odean  MJ, Dornfeld  MP,  et al.  Correlation of symptoms with vitamin D deficiency and symptom response to cholecalciferol treatment: a randomized controlled trial.   Endocr Pract. 2009;15(3):203-212. doi:10.4158/EP.15.3.203PubMedGoogle ScholarCrossref
16.
Bischoff  HA, Stähelin  HB, Dick  W,  et al.  Effects of vitamin D and calcium supplementation on falls: a randomized controlled trial.   J Bone Miner Res. 2003;18(2):343-351. doi:10.1359/jbmr.2003.18.2.343PubMedGoogle ScholarCrossref
17.
Bislev  LS, Langagergaard Rødbro  L, Rolighed  L, Sikjaer  T, Rejnmark  L.  Bone microstructure in response to vitamin D3 supplementation: a randomized placebo-controlled trial.   Calcif Tissue Int. 2019;104(2):160-170. doi:10.1007/s00223-018-0481-6PubMedGoogle ScholarCrossref
18.
Brazier  M, Grados  F, Kamel  S,  et al.  Clinical and laboratory safety of one year’s use of a combination calcium + vitamin D tablet in ambulatory elderly women with vitamin D insufficiency: results of a multicenter, randomized, double-blind, placebo-controlled study.   Clin Ther. 2005;27(12):1885-1893. doi:10.1016/j.clinthera.2005.12.010PubMedGoogle ScholarCrossref
19.
Chapuy  MC, Pamphile  R, Paris  E,  et al.  Combined calcium and vitamin D3 supplementation in elderly women: confirmation of reversal of secondary hyperparathyroidism and hip fracture risk: the Decalyos II study.   Osteoporos Int. 2002;13(3):257-264. doi:10.1007/s001980200023PubMedGoogle ScholarCrossref
20.
Davidson  MB, Duran  P, Lee  ML, Friedman  TC.  High-dose vitamin D supplementation in people with prediabetes and hypovitaminosis D.   Diabetes Care. 2013;36(2):260-266. doi:10.2337/dc12-1204PubMedGoogle ScholarCrossref
21.
Gallagher  JC, Jindal  PS, Smith  LM.  Vitamin D supplementation in young white and African American women.   J Bone Miner Res. 2014;29(1):173-181. doi:10.1002/jbmr.2010PubMedGoogle ScholarCrossref
22.
Gallagher  JC, Sai  A, Templin  T  II, Smith  L.  Dose response to vitamin D supplementation in postmenopausal women: a randomized trial.   Ann Intern Med. 2012;156(6):425-437. doi:10.7326/0003-4819-156-6-201203200-00005PubMedGoogle ScholarCrossref
23.
Gallagher  JC, Peacock  M, Yalamanchili  V, Smith  LM.  Effects of vitamin D supplementation in older African American women.   J Clin Endocrinol Metab. 2013;98(3):1137-1146. doi:10.1210/jc.2012-3106PubMedGoogle ScholarCrossref
24.
Smith  LM, Gallagher  JC, Suiter  C.  Medium doses of daily vitamin D decrease falls and higher doses of daily vitamin D3 increase falls: a randomized clinical trial.   J Steroid Biochem Mol Biol. 2017;173:317-322. doi:10.1016/j.jsbmb.2017.03.015PubMedGoogle ScholarCrossref
25.
Grimnes  G, Figenschau  Y, Almås  B, Jorde  R.  Vitamin D, insulin secretion, sensitivity, and lipids: results from a case-control study and a randomized controlled trial using hyperglycemic clamp technique.   Diabetes. 2011;60(11):2748-2757. doi:10.2337/db11-0650PubMedGoogle ScholarCrossref
26.
Hansen  KE, Johnson  RE, Chambers  KR,  et al.  Treatment of vitamin D insufficiency in postmenopausal women: a randomized clinical trial.   JAMA Intern Med. 2015;175(10):1612-1621. doi:10.1001/jamainternmed.2015.3874PubMedGoogle ScholarCrossref
27.
Hin  H, Tomson  J, Newman  C,  et al.  Optimum dose of vitamin D for disease prevention in older people: BEST-D trial of vitamin D in primary care.   Osteoporos Int. 2017;28(3):841-851. doi:10.1007/s00198-016-3833-yPubMedGoogle ScholarCrossref
28.
Tomson  J, Hin  H, Emberson  J,  et al.  Effects of vitamin D on blood pressure, arterial stiffness, and cardiac function in older people after 1 year: BEST-D (Biochemical Efficacy and Safety Trial of Vitamin D).   J Am Heart Assoc. 2017;6(10):e005707. doi:10.1161/JAHA.117.005707PubMedGoogle Scholar
29.
Clarke  R, Newman  C, Tomson  J,  et al.  Estimation of the optimum dose of vitamin D for disease prevention in older people: rationale, design and baseline characteristics of the BEST-D trial.   Maturitas. 2015;80(4):426-431. doi:10.1016/j.maturitas.2015.01.013PubMedGoogle ScholarCrossref
30.
Jackson  RD, LaCroix  AZ, Gass  M,  et al; Women’s Health Initiative Investigators.  Calcium plus vitamin D supplementation and the risk of fractures.   N Engl J Med. 2006;354(7):669-683. doi:10.1056/NEJMoa055218PubMedGoogle ScholarCrossref
31.
de Boer  IH, Tinker  LF, Connelly  S,  et al; Women’s Health Initiative Investigators.  Calcium plus vitamin D supplementation and the risk of incident diabetes in the Women’s Health Initiative.   Diabetes Care. 2008;31(4):701-707. doi:10.2337/dc07-1829PubMedGoogle ScholarCrossref
32.
Wactawski-Wende  J, Kotchen  JM, Anderson  GL,  et al; Women’s Health Initiative Investigators.  Calcium plus vitamin D supplementation and the risk of colorectal cancer.   N Engl J Med. 2006;354(7):684-696. doi:10.1056/NEJMoa055222PubMedGoogle ScholarCrossref
33.
Chlebowski  RT, Johnson  KC, Kooperberg  C,  et al; Women’s Health Initiative Investigators.  Calcium plus vitamin D supplementation and the risk of breast cancer.   J Natl Cancer Inst. 2008;100(22):1581-1591. doi:10.1093/jnci/djn360PubMedGoogle ScholarCrossref
34.
LaCroix  AZ, Kotchen  J, Anderson  G,  et al.  Calcium plus vitamin D supplementation and mortality in postmenopausal women: the Women’s Health Initiative calcium–vitamin D randomized controlled trial.   J Gerontol A Biol Sci Med Sci. 2009;64(5):559-567. doi:10.1093/gerona/glp006PubMedGoogle ScholarCrossref
35.
Janssen  HCJP, Samson  MM, Verhaar  HJJ.  Muscle strength and mobility in vitamin D–insufficient female geriatric patients: a randomized controlled trial on vitamin D and calcium supplementation.   Aging Clin Exp Res. 2010;22(1):78-84. doi:10.1007/BF03324819PubMedGoogle ScholarCrossref
36.
Jorde  R, Kubiak  J.  No improvement in depressive symptoms by vitamin D supplementation: results from a randomised controlled trial.   J Nutr Sci. 2018;7:e30. doi:10.1017/jns.2018.19PubMedGoogle Scholar
37.
Jorde  R, Sollid  ST, Svartberg  J,  et al.  Vitamin D 20,000 IU per week for five years does not prevent progression from prediabetes to diabetes.   J Clin Endocrinol Metab. 2016;101(4):1647-1655. doi:10.1210/jc.2015-4013PubMedGoogle ScholarCrossref
38.
Jorde  R, Sollid  ST, Svartberg  J, Joakimsen  RM, Grimnes  G, Hutchinson  MY.  Prevention of urinary tract infections with vitamin D supplementation 20,000 IU per week for five years: results from an RCT including 511 subjects.   Infect Dis (Lond). 2016;48(11-12):823-828. doi:10.1080/23744235.2016.1201853PubMedGoogle ScholarCrossref
39.
Kärkkäinen  MK, Tuppurainen  M, Salovaara  K,  et al.  Does daily vitamin D 800 IU and calcium 1000 mg supplementation decrease the risk of falling in ambulatory women aged 65-71 years? a 3-year randomized population-based trial (OSTPRE-FPS).   Maturitas. 2010;65(4):359-365. doi:10.1016/j.maturitas.2009.12.018PubMedGoogle ScholarCrossref
40.
Kärkkäinen  M, Tuppurainen  M, Salovaara  K,  et al.  Effect of calcium and vitamin D supplementation on bone mineral density in women aged 65-71 years: a 3-year randomized population-based trial (OSTPRE-FPS).   Osteoporos Int. 2010;21(12):2047-2055. doi:10.1007/s00198-009-1167-8PubMedGoogle ScholarCrossref
41.
Kjaergaard  M, Waterloo  K, Wang  CE,  et al.  Effect of vitamin D supplement on depression scores in people with low levels of serum 25-hydroxyvitamin D: nested case-control study and randomised clinical trial.   Br J Psychiatry. 2012;201(5):360-368. doi:10.1192/bjp.bp.111.104349PubMedGoogle ScholarCrossref
42.
Krieg  MA, Jacquet  AF, Bremgartner  M, Cuttelod  S, Thiébaud  D, Burckhardt  P.  Effect of supplementation with vitamin D3 and calcium on quantitative ultrasound of bone in elderly institutionalized women: a longitudinal study.   Osteoporos Int. 1999;9(6):483-488.PubMedGoogle Scholar
43.
Lips  P, Binkley  N, Pfeifer  M,  et al.  Once-weekly dose of 8400 IU vitamin D(3) compared with placebo: effects on neuromuscular function and tolerability in older adults with vitamin D insufficiency.   Am J Clin Nutr. 2010;91(4):985-991. doi:10.3945/ajcn.2009.28113PubMedGoogle ScholarCrossref
44.
Lips  P, Graafmans  WC, Ooms  ME, Bezemer  PD, Bouter  LM.  Vitamin D supplementation and fracture incidence in elderly persons: a randomized, placebo-controlled clinical trial.   Ann Intern Med. 1996;124(4):400-406. doi:10.7326/0003-4819-124-4-199602150-00003PubMedGoogle ScholarCrossref
45.
Ooms  ME, Roos  JC, Bezemer  PD, van der Vijgh  WJ, Bouter  LM, Lips  P.  Prevention of bone loss by vitamin D supplementation in elderly women: a randomized double-blind trial.   J Clin Endocrinol Metab. 1995;80(4):1052-1058.PubMedGoogle Scholar
46.
Manson  JE, Cook  NR, Lee  IM,  et al; VITAL Research Group.  Vitamin D supplements and prevention of cancer and cardiovascular disease.   N Engl J Med. 2019;380(1):33-44. doi:10.1056/NEJMoa1809944PubMedGoogle ScholarCrossref
47.
Manson  JE, Cook  NR, Lee  IM,  et al; VITAL Research Group.  Marine n-3 fatty acids and prevention of cardiovascular disease and cancer.   N Engl J Med. 2019;380(1):23-32. doi:10.1056/NEJMoa1811403PubMedGoogle ScholarCrossref
48.
Manson  JE, Bassuk  SS, Lee  IM,  et al.  The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease.   Contemp Clin Trials. 2012;33(1):159-171. doi:10.1016/j.cct.2011.09.009PubMedGoogle ScholarCrossref
49.
Donlon  CM, LeBoff  MS, Chou  SH,  et al.  Baseline characteristics of participants in the VITamin D and OmegA-3 TriaL (VITAL): effects on bone structure and architecture.   Contemp Clin Trials. 2018;67:56-67. doi:10.1016/j.cct.2018.02.003PubMedGoogle ScholarCrossref
50.
Bassuk  SS, Manson  JE, Lee  IM,  et al.  Baseline characteristics of participants in the VITamin D and OmegA-3 TriaL (VITAL).   Contemp Clin Trials. 2016;47:235-243. doi:10.1016/j.cct.2015.12.022PubMedGoogle ScholarCrossref
51.
Pfeifer  M, Begerow  B, Minne  HW, Suppan  K, Fahrleitner-Pammer  A, Dobnig  H.  Effects of a long-term vitamin D and calcium supplementation on falls and parameters of muscle function in community-dwelling older individuals.   Osteoporos Int. 2009;20(2):315-322. doi:10.1007/s00198-008-0662-7PubMedGoogle ScholarCrossref
52.
Pfeifer  M, Begerow  B, Minne  HW, Abrams  C, Nachtigall  D, Hansen  C.  Effects of a short-term vitamin D and calcium supplementation on body sway and secondary hyperparathyroidism in elderly women.   J Bone Miner Res. 2000;15(6):1113-1118. doi:10.1359/jbmr.2000.15.6.1113PubMedGoogle ScholarCrossref
53.
Pittas  AG, Dawson-Hughes  B, Sheehan  P,  et al; D2d Research Group.  Vitamin D supplementation and prevention of type 2 diabetes.   N Engl J Med. 2019;381(6):520-530. doi:10.1056/NEJMoa1900906PubMedGoogle ScholarCrossref
54.
Khaw  KT, Stewart  AW, Waayer  D,  et al.  Effect of monthly high-dose vitamin D supplementation on falls and non-vertebral fractures: secondary and post-hoc outcomes from the randomised, double-blind, placebo-controlled ViDA trial.   Lancet Diabetes Endocrinol. 2017;5(6):438-447. doi:10.1016/S2213-8587(17)30103-1PubMedGoogle ScholarCrossref
55.
Scragg  R, Stewart  AW, Waayer  D,  et al.  Effect of monthly high-dose vitamin D supplementation on cardiovascular disease in the Vitamin D Assessment Study: a randomized clinical trial.   JAMA Cardiol. 2017;2(6):608-616. doi:10.1001/jamacardio.2017.0175PubMedGoogle ScholarCrossref
56.
Sluyter  JD, Camargo  CA  Jr, Stewart  AW,  et al.  Effect of monthly, high-dose, long-term vitamin D supplementation on central blood pressure parameters: a randomized controlled trial substudy.   J Am Heart Assoc. 2017;6(10):e006802. doi:10.1161/JAHA.117.006802PubMedGoogle Scholar
57.
Shea  MK, Fielding  RA, Dawson-Hughes  B.  The effect of vitamin D supplementation on lower-extremity power and function in older adults: a randomized controlled trial.   Am J Clin Nutr. 2019;109(2):369-379. doi:10.1093/ajcn/nqy290PubMedGoogle ScholarCrossref
58.
Wood  AD, Secombes  KR, Thies  F,  et al.  Vitamin D3 supplementation has no effect on conventional cardiovascular risk factors: a parallel-group, double-blind, placebo-controlled RCT.   J Clin Endocrinol Metab. 2012;97(10):3557-3568. doi:10.1210/jc.2012-2126PubMedGoogle ScholarCrossref
59.
Macdonald  HM, Gryka  A, Tang  JCY, Aucott  LS, Fraser  WD, Wood  AD.  Longevity of daily oral vitamin D3 supplementation: differences in 25OHD and 24,25(OH)2D observed 2 years after cessation of a 1-year randomised controlled trial (VICtORy RECALL).   Osteoporos Int. 2017;28(12):3361-3372. doi:10.1007/s00198-017-4201-2PubMedGoogle ScholarCrossref
60.
Aloia  J, Fazzari  M, Islam  S,  et al.  Vitamin D supplementation in elderly Black women does not prevent bone loss: a randomized controlled trial.   J Bone Miner Res. 2018;33(11):1916-1922. doi:10.1002/jbmr.3521PubMedGoogle ScholarCrossref
61.
Aloia  JF, Talwar  SA, Pollack  S, Yeh  J.  A randomized controlled trial of vitamin D3 supplementation in African American women.   Arch Intern Med. 2005;165(14):1618-1623. doi:10.1001/archinte.165.14.1618PubMedGoogle ScholarCrossref
62.
Talwar  SA, Aloia  JF, Pollack  S, Yeh  JK.  Dose response to vitamin D supplementation among postmenopausal African American women.   Am J Clin Nutr. 2007;86(6):1657-1662. doi:10.1093/ajcn/86.5.1657PubMedGoogle ScholarCrossref
63.
Borgi  L, McMullan  C, Wohlhueter  A, Curhan  GC, Fisher  ND, Forman  JP.  Effect of vitamin D on endothelial function: a randomized, double-blind, placebo-controlled trial.   Am J Hypertens. 2017;30(2):124-129. doi:10.1093/ajh/hpw135PubMedGoogle ScholarCrossref
64.
McMullan  CJ, Borgi  L, Curhan  GC, Fisher  N, Forman  JP.  The effect of vitamin D on renin-angiotensin system activation and blood pressure: a randomized control trial.   J Hypertens. 2017;35(4):822-829. doi:10.1097/HJH.0000000000001220PubMedGoogle ScholarCrossref
65.
Gagnon  C, Daly  RM, Carpentier  A,  et al.  Effects of combined calcium and vitamin D supplementation on insulin secretion, insulin sensitivity and β-cell function in multi-ethnic vitamin D–deficient adults at risk for type 2 diabetes: a pilot randomized, placebo-controlled trial.   PLoS One. 2014;9(10):e109607. doi:10.1371/journal.pone.0109607PubMedGoogle Scholar
66.
Honkanen  R, Alhava  E, Parviainen  M, Talasniemi  S, Mönkkönen  R.  The necessity and safety of calcium and vitamin D in the elderly.   J Am Geriatr Soc. 1990;38(8):862-866. doi:10.1111/j.1532-5415.1990.tb05700.xPubMedGoogle ScholarCrossref
67.
Kearns  MD, Binongo  JN, Watson  D,  et al.  The effect of a single, large bolus of vitamin D in healthy adults over the winter and following year: a randomized, double-blind, placebo-controlled trial.   Eur J Clin Nutr. 2015;69(2):193-197. doi:10.1038/ejcn.2014.209PubMedGoogle ScholarCrossref
68.
Knutsen  KV, Madar  AA, Lagerløv  P,  et al.  Does vitamin D improve muscle strength in adults? a randomized, double-blind, placebo-controlled trial among ethnic minorities in Norway.   J Clin Endocrinol Metab. 2014;99(1):194-202. doi:10.1210/jc.2013-2647PubMedGoogle ScholarCrossref
69.
Lehmann  U, Hirche  F, Stangl  GI, Hinz  K, Westphal  S, Dierkes  J.  Bioavailability of vitamin D(2) and D(3) in healthy volunteers, a randomized placebo-controlled trial.   J Clin Endocrinol Metab. 2013;98(11):4339-4345. doi:10.1210/jc.2012-4287PubMedGoogle ScholarCrossref
70.
Lerchbaum  E, Pilz  S, Trummer  C,  et al.  Vitamin D and testosterone in healthy men: a randomized controlled trial.   J Clin Endocrinol Metab. 2017;102(11):4292-4302. doi:10.1210/jc.2017-01428PubMedGoogle ScholarCrossref
71.
Martineau  AR, Wilkinson  RJ, Wilkinson  KA,  et al.  A single dose of vitamin D enhances immunity to mycobacteria.   Am J Respir Crit Care Med. 2007;176(2):208-213. doi:10.1164/rccm.200701-007OCPubMedGoogle ScholarCrossref
72.
Mason  C, Xiao  L, Imayama  I,  et al.  Vitamin D3 supplementation during weight loss: a double-blind randomized controlled trial.   Am J Clin Nutr. 2014;99(5):1015-1025. doi:10.3945/ajcn.113.073734PubMedGoogle ScholarCrossref
73.
Moreira-Lucas  TS, Duncan  AM, Rabasa-Lhoret  R,  et al.  Effect of vitamin D supplementation on oral glucose tolerance in individuals with low vitamin D status and increased risk for developing type 2 diabetes (EVIDENCE): a double-blind, randomized, placebo-controlled clinical trial.   Diabetes Obes Metab. 2017;19(1):133-141. doi:10.1111/dom.12794PubMedGoogle ScholarCrossref
74.
Ng  K, Scott  JB, Drake  BF,  et al.  Dose response to vitamin D supplementation in African Americans: results of a 4-arm, randomized, placebo-controlled trial.   Am J Clin Nutr. 2014;99(3):587-598. doi:10.3945/ajcn.113.067777PubMedGoogle ScholarCrossref
75.
Chandler  PD, Giovannucci  EL, Scott  JB,  et al.  Null association between vitamin D and PSA levels among black men in a vitamin D supplementation trial.   Cancer Epidemiol Biomarkers Prev. 2014;23(9):1944-1947. doi:10.1158/1055-9965.EPI-14-0522PubMedGoogle ScholarCrossref
76.
Chandler  PD, Scott  JB, Drake  BF,  et al.  Impact of vitamin D supplementation on inflammatory markers in African Americans: results of a four-arm, randomized, placebo-controlled trial.   Cancer Prev Res (Phila). 2014;7(2):218-225. doi:10.1158/1940-6207.CAPR-13-0338-TPubMedGoogle ScholarCrossref
77.
Nowak  A, Boesch  L, Andres  E,  et al.  Effect of vitamin D3 on self-perceived fatigue: a double-blind randomized placebo-controlled trial.   Medicine (Baltimore). 2016;95(52):e5353. doi:10.1097/MD.0000000000005353PubMedGoogle Scholar
78.
Pilz  S, Gaksch  M, Kienreich  K,  et al.  Effects of vitamin D on blood pressure and cardiovascular risk factors: a randomized controlled trial.   Hypertension. 2015;65(6):1195-1201. doi:10.1161/HYPERTENSIONAHA.115.05319PubMedGoogle ScholarCrossref
79.
Grübler  MR, Gaksch  M, Kienreich  K,  et al.  Effects of vitamin D supplementation on glycated haemoglobin and fasting glucose levels in hypertensive patients: a randomized controlled trial.   Diabetes Obes Metab. 2016;18(10):1006-1012. doi:10.1111/dom.12709PubMedGoogle ScholarCrossref
80.
Grübler  MR, Gaksch  M, Kienreich  K,  et al.  Effects of vitamin D supplementation on plasma aldosterone and renin—a randomized placebo-controlled trial.   J Clin Hypertens (Greenwich). 2016;18(7):608-613. doi:10.1111/jch.12825PubMedGoogle ScholarCrossref
81.
Grübler  MR, Gaksch  M, Kienreich  K,  et al.  Effects of vitamin D3 on asymmetric- and symmetric dimethylarginine in arterial hypertension.   J Steroid Biochem Mol Biol. 2018;175:157-163. doi:10.1016/j.jsbmb.2016.12.014PubMedGoogle ScholarCrossref
82.
Raed  A, Bhagatwala  J, Zhu  H,  et al.  Dose responses of vitamin D3 supplementation on arterial stiffness in overweight African Americans with vitamin D deficiency: a placebo controlled randomized trial.   PLoS One. 2017;12(12):e0188424. doi:10.1371/journal.pone.0188424PubMedGoogle Scholar
83.
Bhagatwala  J, Zhu  H, Parikh  SJ,  et al.  Dose and time responses of vitamin D biomarkers to monthly vitamin D3 supplementation in overweight/obese African Americans with suboptimal vitamin D status: a placebo controlled randomized clinical trial.   BMC Obes. 2015;2:27. doi:10.1186/s40608-015-0056-2PubMedGoogle ScholarCrossref
84.
Tran  B, Armstrong  BK, Ebeling  PR,  et al.  Effect of vitamin D supplementation on antibiotic use: a randomized controlled trial.   Am J Clin Nutr. 2014;99(1):156-161. doi:10.3945/ajcn.113.063271PubMedGoogle ScholarCrossref
85.
Tran  B, Armstrong  BK, Carlin  JB,  et al.  Recruitment and results of a pilot trial of vitamin D supplementation in the general population of Australia.   J Clin Endocrinol Metab. 2012;97(12):4473-4480. doi:10.1210/jc.2012-2682PubMedGoogle ScholarCrossref
86.
Wamberg  L, Kampmann  U, Stødkilde-Jørgensen  H, Rejnmark  L, Pedersen  SB, Richelsen  B.  Effects of vitamin D supplementation on body fat accumulation, inflammation, and metabolic risk factors in obese adults with low vitamin D levels—results from a randomized trial.   Eur J Intern Med. 2013;24(7):644-649. doi:10.1016/j.ejim.2013.03.005PubMedGoogle ScholarCrossref
87.
Wamberg  L, Pedersen  SB, Richelsen  B, Rejnmark  L.  The effect of high-dose vitamin D supplementation on calciotropic hormones and bone mineral density in obese subjects with low levels of circulating 25-hydroxyvitamin D: results from a randomized controlled study.   Calcif Tissue Int. 2013;93(1):69-77. doi:10.1007/s00223-013-9729-3PubMedGoogle ScholarCrossref
88.
Witham  MD, Adams  F, Kabir  G, Kennedy  G, Belch  JJ, Khan  F.  Effect of short-term vitamin D supplementation on markers of vascular health in South Asian women living in the UK—a randomised controlled trial.   Atherosclerosis. 2013;230(2):293-299. doi:10.1016/j.atherosclerosis.2013.08.005PubMedGoogle ScholarCrossref
89.
LeBoff  MS, Murata  EM, Cook  NR,  et al.  VITamin D and OmegA-3 TriaL (VITAL): effects of vitamin D supplements on risk of falls in the US population.   J Clin Endocrinol Metab. 2020;105(9):2929-2938. doi:10.1210/clinem/dgaa311PubMedGoogle ScholarCrossref
90.
Scragg  R, Khaw  KT, Toop  L,  et al.  Monthly high-dose vitamin D supplementation and cancer risk: a post hoc analysis of the Vitamin D Assessment randomized clinical trial.   JAMA Oncol. 2018;4(11):e182178. doi:10.1001/jamaoncol.2018.2178PubMedGoogle Scholar
91.
Okereke  OI, Reynolds  CF  III, Mischoulon  D,  et al.  Effect of long-term vitamin D3 supplementation vs placebo on risk of depression or clinically relevant depressive symptoms and on change in mood scores: a randomized clinical trial.   JAMA. 2020;324(5):471-480. doi:10.1001/jama.2020.10224PubMedGoogle ScholarCrossref
92.
Guirguis-Blake  JM, Michael  YL, Perdue  LA, Coppola  EL, Beil  TL.  Interventions to prevent falls in older adults: updated evidence report and systematic review for the US Preventive Services Task Force.   JAMA. 2018;319(16):1705-1716. doi:10.1001/jama.2017.21962PubMedGoogle ScholarCrossref
93.
Grossman  DC, Curry  SJ, Owens  DK,  et al; US Preventive Services Task Force.  Interventions to prevent falls in community-dwelling older adults: US Preventive Services Task Force recommendation statement.   JAMA. 2018;319(16):1696-1704. doi:10.1001/jama.2018.3097PubMedGoogle ScholarCrossref
94.
Atef  SH.  Vitamin D assays in clinical laboratory: past, present and future challenges.   J Steroid Biochem Mol Biol. 2018;175:136-137. doi:10.1016/j.jsbmb.2017.02.011PubMedGoogle ScholarCrossref
95.
Kahwati  LC, Weber  RP, Pan  H,  et al.  Vitamin D, calcium, or combined supplementation for the primary prevention of fractures in community-dwelling adults: evidence report and systematic review for the US Preventive Services Task Force.   JAMA. 2018;319(15):1600-1612. doi:10.1001/jama.2017.21640PubMedGoogle ScholarCrossref
96.
Guyatt  GH, Oxman  AD, Kunz  R,  et al.  GRADE guidelines 6: rating the quality of evidence—imprecision.   J Clin Epidemiol. 2011;64(12):1283-1293. doi:10.1016/j.jclinepi.2011.01.012PubMedGoogle ScholarCrossref
US Preventive Services Task Force
Evidence Report
April 13, 2021

Screening for Vitamin D Deficiency in Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force

Author Affiliations
  • 1RTI International–University of North Carolina at Chapel Hill Evidence-based Practice Center, Chapel Hill, North Carolina
  • 2RTI International, Research Triangle Park, North Carolina
  • 3Kaiser Permanente Center for Health Research, Portland, Oregon
  • 4Cecil G. Sheps Center for Health Services Research, University of North Carolina at Chapel Hill
  • 5Gillings School of Global Public Health and Eshelman School of Pharmacy, University of North Carolina at Chapel Hill
JAMA. 2021;325(14):1443-1463. doi:10.1001/jama.2020.26498
Abstract

Importance  Low serum vitamin D levels have been associated with adverse clinical outcomes; identifying and treating deficiency may improve outcomes.

Objective  To review the evidence about screening for vitamin D deficiency in adults.

Data Sources  PubMed, EMBASE, the Cochrane Library, and trial registries through March 12, 2020; bibliographies from retrieved articles, outside experts, and surveillance of the literature through November 30, 2020.

Study Selection  Fair- or good-quality, English-language randomized clinical trials (RCTs) of screening with serum 25-hydroxyvitamin D (25[OH]D) compared with no screening, or treatment with vitamin D (with or without calcium) compared with placebo or no treatment conducted in nonpregnant adults; nonrandomized controlled intervention studies for harms only. Treatment was limited to studies enrolling or analyzing participants with low serum vitamin D levels.

Data Extraction and Synthesis  Two reviewers assessed titles/abstracts and full-text articles, extracted data, and assessed study quality; when at least 3 similar studies were available, meta-analyses were conducted.

Main Outcomes and Measures  Mortality, incident fractures, falls, diabetes, cardiovascular events, cancer, depression, physical functioning, and infection.

Results  Forty-six studies (N = 16 205) (77 publications) were included. No studies directly evaluated the health benefits or harms of screening. Among community-dwelling populations, treatment was not significantly associated with mortality (pooled absolute risk difference [ARD], 0.3% [95% CI, −0.6% to 1.1%]; 8 RCTs, n = 2006), any fractures (pooled ARD, −0.3% [95% CI, −2.1% to 1.6%]; 6 RCTs, n = 2186), incidence of diabetes (pooled ARD, 0.1% [95% CI, −1.3% to 1.6%]; 5 RCTs, n = 3356), incidence of cardiovascular disease (2 RCTs; hazard ratio, 1.00 [95% CI, 0.74 to 1.35] and 1.09 [95% CI, 0.68 to 1.76]), incidence of cancer (2 RCTs; hazard ratio, 0.97 [95% CI, 0.68 to 1.39] and 1.01 [95% CI, 0.65 to 1.58], or depression (3 RCTs, various measures reported). The pooled ARD for incidence of participants with 1 or more falls was −4.3% (95% CI, −11.6% to 2.9%; 6 RCTs). The evidence was mixed for the effect of treatment on physical functioning (2 RCTs) and limited for the effect on infection (1 RCT). The incidence of adverse events and kidney stones was similar between treatment and control groups.

Conclusions and Relevance  No studies evaluated the direct benefits or harms of screening for vitamin D deficiency. Among asymptomatic, community-dwelling populations with low vitamin D levels, the evidence suggests that treatment with vitamin D has no effect on mortality or the incidence of fractures, falls, depression, diabetes, cardiovascular disease, cancer, or adverse events. The evidence is inconclusive about the effect of treatment on physical functioning and infection.

Introduction

Vitamin D has a variety of actions on calcium homeostasis, bone metabolism, and other cellular regulatory functions.1-3 Vitamin D deficiency refers to serum levels of vitamin D (serum total hydroxyvitamin D, or 25[OH]D) that are inadequate to support bodily needs. Serum total 25(OH)D is currently considered the best marker of vitamin D status.4,5 However, there is no consensus regarding the serum level of 25(OH)D that represents optimal health or deficiency.1,5,6

The rationale for screening for vitamin D deficiency among asymptomatic adults is to identify low serum vitamin D levels that place persons at risk for deficiency and offer treatment before potential adverse clinical outcomes (falls, fractures, and other outcomes) occur. In 2014, the US Preventive Services Task Force (USPSTF) concluded that the evidence was insufficient to assess the balance of benefits and harms of screening for vitamin D deficiency in adults (I statement). This review was conducted for the USPSTF to inform an update of its 2014 recommendation.7-9

Methods
Scope of the Review

The analytic framework and key questions (KQs) that guided the review are shown in Figure 1. Detailed methods, evidence tables, supplemental analyses, and contextual information are available in the full evidence report.10

Data Sources and Searches

PubMed, the Cochrane Library, and EMBASE were searched for English-language articles published from January 1, 2013, through March 12, 2020. ClinicalTrials.gov, Cochrane Register of Controlled Trials, and the World Health Organization International Clinical Trials Registry Platform were also searched. To supplement systematic electronic searches (eMethods in the Supplement), reference lists of pertinent articles and studies suggested by reviewers were searched. Ongoing surveillance was conducted through article alerts and targeted searches of journals to identify major studies published in the interim that may affect the conclusions or understanding of the evidence and the related USPSTF recommendation. The last surveillance was conducted on November 30, 2020.

Study Selection

Two investigators independently reviewed titles, abstracts, and full-text articles using prespecified inclusion criteria for each KQ (eMethods in the Supplement); disagreements about inclusion were resolved by discussion or by a third reviewer. For all KQs, randomized clinical trials (RCTs) conducted in nonpregnant adults were eligible for selection. For KQ1 and KQ2, studies that were conducted among participants not known to have vitamin D deficiency were eligible for selection. For KQ3 and KQ4, studies that either enrolled participants with known deficiency (defined as serum vitamin D level less than 30 ng/mL [to convert to nmol/L, multiply by 2.496]) or reported findings for a subgroup of participants with known deficiency were eligible, as were nested case-control studies within RCTs. For KQ1 and KQ2, studies that evaluated screening using total serum 25(OH)D were eligible, and for KQ3 and KQ4, studies that evaluated treatment with oral or injectable vitamin D2 or vitamin D3 of any dosage with or without concomitant calcium were eligible. For KQ1 and KQ3, studies reporting health outcomes, such as mortality, falls, fractures, incident disease (eg, diabetes, cancer, cardiovascular event, and others), and validated quality of life, and self-reported physical functioning measures were eligible; studies reporting only changes in serum vitamin D levels, intermediate physiologic outcomes (eg, bone mineral density, blood pressure), or physical fitness/muscle strength measures were not eligible. For KQ2 and KQ4, studies reporting harms from screening (eg, anxiety, labeling) or harms from treatment (eg, toxicity, nephrolithiasis, adverse events) were eligible; nonrandomized controlled intervention studies, cohort studies, and case-control studies were also eligible for selection.

English-language studies that met all study selection criteria, were fair or good methodological quality, and were conducted in countries categorized as very highly developed by the 2016 United Nations Human Development Index were included.11 Studies included in the prior 2014 review for the USPSTF were reassessed against the study selection and methodological quality criteria for this update.

Data Extraction and Quality Assessment

For each included study, 1 reviewer abstracted relevant study characteristics (ie, population, intervention, comparator) and data for eligible outcomes into a structured form. A second reviewer checked all data for completeness and accuracy. Two senior reviewers independently assessed each study’s methodological quality using predefined criteria established by the USPSTF (eMethods in the Supplement) and others.12 Disagreements in study quality ratings were resolved through discussion or with a third senior reviewer.

Data Synthesis and Analysis

Data were synthesized in tabular and narrative formats. When at least 3 similar studies were available, a quantitative synthesis was performed using random-effects models with the inverse-variance weighted method of DerSimonian and Laird in Stata version 16 (StataCorp) to generate pooled estimates of the absolute risk difference (ARD), the relative risk ratio (RR), the incidence rate difference, or the incidence rate ratio.13 Analyses were stratified based on study population (community dwelling vs institutionalized) when possible. For rare event outcomes, such as mortality, sensitivity analyses were also conducted using other estimators and models with and without continuity corrections to assess robustness of the main findings. Significance testing was based on the exclusion of the null value by the 95% confidence interval around the pooled estimate.

The strength of evidence was assessed based on the Agency for Healthcare Quality and Research Methods Guide for Effectiveness and Comparative Effectiveness Reviews, which specifies the assessment of study limitations, directness, consistency, precision, and reporting bias for each intervention comparison and major outcome of interest.14 Two senior reviewers independently developed initial strength-of-evidence assessments for each relevant outcome and comparison across the KQs; disagreements were resolved through discussion or input of a third senior reviewer.

Results

Forty-six studies (N = 16 205) from 77 publications were included (Figure 2). Twenty-seven studies of treatment benefits (KQ3)15-59 and 36 studies evaluating the harms of treatment (KQ4)15-19,21-29,35,36,39-43,58-88 were identified. Study characteristics of included RCTs are described in Table 1. A list of full-text articles screened but excluded is provided in the Supplement.

Benefits of Screening

Key Question 1a. Does screening for vitamin D deficiency improve health outcomes?

Key Question 1b. Does screening efficacy vary among patient subpopulations at higher risk for vitamin D deficiency (eg, persons residing in institutions, persons with obesity, persons with low levels of sun exposure, or older adults) or vary by race/ethnicity?

No studies were identified.

Harms of Screening

Key Question 2. What are the harms of screening for vitamin D deficiency?

No studies were identified.

Benefits of Treatment

Key Question 3a. Does treatment of vitamin D deficiency with vitamin D improve health outcomes?

Key Question 3b. Does treatment efficacy vary among patient subpopulations at higher risk for vitamin D deficiency (eg, persons residing in institutions, persons with obesity, persons with low levels of sun exposure, or older adults) or vary by race/ethnicity?

Twenty-six RCTs15-29,35-59 and 1 nested case-control study from the Women’s Health Initiative (WHI) Calcium and Vitamin D RCT30-34 reported eligible outcomes. Nine RCTs were assessed as good quality,17,20,22,26,27,41,46,54,57 and the rest were assessed as fair quality. Detailed study characteristics, outcomes, and individual study methodological quality are described in eTables 1-7 and 13-17 in the Supplement.

Five studies were conducted exclusively or predominantly among populations in nursing homes or homes for the elderly (ie, “institutionalized” settings)16,19,35,42; the rest were conducted exclusively or predominantly among community-dwelling populations. The mean age of included populations ranged from 36 to 85, but 54% were conducted among study populations with a mean age of 60 years or older. Twelve studies were conducted exclusively among female populations.16-19,21,22,26,30,39,42,52,58 The race/ethnicity of the studied populations included multiple races and ethnicities in 9 studies,15,21,22,26,30,46,53,54,57 was exclusively White in 1 study,58 was mostly Latino in 1 study,20 and was not reported in the remaining studies.

Nine studies17,18,21,22,35,36,43,52,57 enrolled participants with serum vitamin D levels less than 20 ng/mL, and 5 studies enrolled participants using thresholds between 20 and 30 ng/mL.15,20,26,41,51 Eight studies did not require participants to meet specific serum vitamin D–level criteria for enrollment, but the mean baseline serum vitamin D levels reported among the enrolled populations suggested that 90% or more of the enrolled participants had baseline serum levels less than 30 ng/mL.16,19,25,27,39,42,44,58 Five studies did not require participants to be vitamin D deficient for enrollment but reported results separately for the subgroup of participants with serum levels less than 20 ng/mL.30,37,46,53,54 Vitamin D assays used by studies varied.

All studies used vitamin D3 as part of the active treatment intervention. Most studies used daily doses, which varied from as low as 400 IU to as high as 4000 IU. Two studies used a high initial loading dose, followed by lower monthly doses26,54; 1 of these studies also titrated the dose to reach a target serum level of 30 ng/mL.26 One study titrated the weekly dose to achieve a target serum level between 65 ng/mL and 90 ng/mL, resulting in an average weekly dose of 88 865 IU.20 The rest of the studies used weekly, twice weekly, twice monthly, or monthly doses. Two studies used a no-intervention control group39,42; the rest used placebo controls. Four studies included various doses of oral calcium as part of the active treatment intervention.18,19,39,42 Six studies provided calcium to both the active vitamin D treatment group and control group.16,21,22,43,51,52 Treatment duration ranged from 8 weeks to 7 years.

All-Cause Mortality

Twelve RCTs18,19,21,22,25-27,35,39,42-44 reported all-cause mortality outcomes over 4 months to 3 years (eTable 4 in the Supplement); however, none evaluated mortality as a primary study aim. The pooled ARD comparing vitamin D treatment with control among studies conducted in community-dwelling populations was 0.3 percentage points (95% CI, −0.6% to 1.1%; 2006 participants; 8 RCTs; I2 = 0%), and the pooled RR was 1.13 (95% CI, 0.39 to 3.28) (Figure 3). Because events were rare, sensitivity analyses were conducted using alternative pooling methods, and ARD estimates were stable (eResults and eTables 18 and 19 in the Supplement). The findings from the WHI nested case-control study were consistent with the findings from the RCTs.30,34

Fractures

Nine RCTs17,19,26,27,35,44,51,52,54 reported fracture outcomes over 12 weeks to 3.3 years (eTable 5 in the Supplement); studies varied by type of fracture reported and ascertainment methods. The pooled ARD comparing vitamin D treatment with control among studies conducted in community-dwelling participants for incidence of fractures was −0.3 percentage points (95% CI, −2.1% to 1.6%; 2186 participants; 6 RCTs; I2 = 13.0%), and the pooled RR was 0.84 (95% CI, 0.58 to 1.21) (Figure 4). Findings from the WHI nested case-control study were consistent with findings from the RCTs.30 Four RCTs19,35,44,52 reported the incidence of hip fracture, but only 1 was conducted among community-dwelling populations52; only 1 hip fracture occurred, leading to an imprecise effect estimate (eFigure 1 in the Supplement).

Falls

Eleven RCTs reported fall outcomes over 1 to 3 years among either community-dwelling or institutionalized populations (eTable 6 in the Supplement).16,19,26,27,39,46,51,52,54,57,58,89 Four RCTs reported the number of participants who experienced 1 or more falls,19,27,54,57 1 RCT reported the number of participants who experienced 2 or more falls,89 2 RCTs reported the total number of falls experienced in each treatment group,26,58 and 4 RCTs reported both outcomes.16,39,51,52 The pooled ARD comparing vitamin D treatment with control for the incidence of participants with 1 or more falls among community-dwelling populations was −4.3 percentage points (95% CI, −11.6% to 2.9%; 2633 participants; 6 RCTs; I2 = 70.1%), and the RR was 0.90 (95% CI, 0.75 to 1.08) (Figure 5). Heterogeneity was high, as indicated by the I2 statistic.

The 2 studies observing a more than 10–percentage-point absolute decrease in incidence were conducted by the same research team using similar methods and calcium controls51,52; findings were statistically significant in only 1 of the studies.51 The other 4 studies observed smaller effects ranging from a decrease of 4.6 percentage points to an increase of 3.1 percentage points; these findings were not statistically significant.27,39,54,57 In the RCT reporting on the incidence of 2 or more falls, no significant difference was observed between vitamin D and placebo groups among participants with baseline vitamin D levels less than 12 ng/mL (adjusted odds ratio, 1.03 [95% CI, 0.59 to 1.79]) or for participants with baseline levels between 12 and 20 ng/mL (adjusted odds ratio, 1.13 [95% CI, 0.87 to 1.48]).46,89

Vitamin D treatment was associated with fewer total falls compared with control in studies conducted among community-dwelling populations (incidence rate difference, 0.10 fewer falls per person-year [95% CI, −0.19 to −0.002]; 2838 person-years; 6 RCTs; I2 = 76.9%; incidence rate ratio, 0.76 [95% CI, 0.57 to 0.94]) (Figure 6).

Other Morbidities

Studies also reported on the incidence of other morbidities, including diabetes, cardiovascular disease, cancer, depression, and infection, and on physical functioning (eTable 7 in the Supplement). Five RCTs, all conducted among community-dwelling populations, reported on incident diabetes over 1 to 7 years, although ascertainment methods varied.20,31,37,53,58 The pooled ARD for incident diabetes was 0.1 percentage points (95% CI, −1.3% to 1.6%; 3356 participants; 5 RCTs; I2 = 0%), and the pooled RR was 0.96 (0.80 to 1.15) (eFigure 2 in the Supplement).

Two RCTs conducted among community-dwelling populations reported the effect of vitamin D treatment on the incidence of cardiovascular disease and cancer among subgroups of participants with serum levels less than 20 ng/mL at baseline.46,53 No statistically significant differences in cardiovascular events (subgroup n = 2000; hazard ratio [HR], 1.09 [95% CI, 0.68 to 1.76] over 5.3 years46 and subgroup n = 1270; HR, 1.00 [95% CI, 0.74 to 1.53] over 3.3 years54,55) or incident invasive cancer (HR, 1.01 [95% CI, 0.65 to 1.58]90 and HR, 0.97 [95% CI, 0.68 to 1.39]46) were observed in either trial. No statistically significant associations were observed between vitamin D treatment and incident breast or colorectal cancer over 7 years in the WHI nested case-control study among participants with low serum vitamin D levels at baseline.32,33

Three RCTs36,41 (subgroup n = 1328,46,91 n = 243,39 and n = 40834) reported on depression outcomes over 5.3 years, 16 weeks, and 26 weeks, respectively, and found no statistically significant differences between treatment and control as measured by various validated depression symptom rating scales. Two RCTs (n = 23024 and n = 10013) reported measures of physical functioning (eg, fibromyalgia impact questionnaire at 8 weeks,13 modified Stanford Health Assessment Questionnaire24 at 1 year); findings were mixed. One RCT37 (subgroup n = 173) reported on incident urinary tract infection over 5 years of follow-up (HR, 0.53 [95% CI, 0.17 to 1.64]).

Variation in Benefits by Subgroup

One of the RCTs conducted in institutional settings reported mortality (1 participant), but this was not reported by group, so it could not be included in the quantitative synthesis.35 Among the 3 RCTs conducted among institutionalized populations, an absolute risk decrease ranging from 2.2 to 5.6 percentage points was observed; however, no individual study estimates were precise enough to exclude the null effect (Figure 3). When pooled, the ARD was −2.8 percentage points (95% CI, −5.5% to −0.2%; 3409 participants; I2 = 0%). The RR was 0.86 (95% CI, 0.74 to 0.99). Data were limited for evaluating effects among other subgroups, but for mortality, fractures, and falls, no differences between men and women or among studies using lower thresholds to define deficiency (eg, <20 ng/mL) for enrollment or calcium cointerventions were observed (eFigures 3-8 in the Supplement).

Only 1 study reported benefits of vitamin D treatment stratified by race or ethnicity.22,23 In this study, no mortality events occurred among either the White or African American populations enrolled. With the exception of 1 study conducted primarily among a Latino population,20 the studies reporting the race or ethnicity of the enrolled population were conducted among exclusively or majority White populations. Thus, the ability to determine the influence of race/ethnicity on benefit outcomes was limited.

Harms of Treatment

Key Question 4a. What are the harms of treatment of vitamin D deficiency with vitamin D?

Key Question 4b. Do harms vary among patient subpopulations at higher risk for vitamin D deficiency (eg, persons residing in institutions, persons with obesity, persons with low levels of sun exposure, or older adults) or vary by race/ethnicity?

Thirty-six RCTs15-19,21-29,35,36,39-43,58-88 reported on harms of treatment; 16 of these were also included for KQ3. Nine of the studies were assessed as good quality17,22,26,27,41,63,74,77,84; the rest were assessed as fair quality. See the Supplement for additional study characteristics (eTables 1-3) and individual study quality ratings (eTables 15 and 16).

Four studies were conducted among institutionalized populations,16,19,35,42 2 were conducted among mixed community-dwelling and institutionalized populations,43,66 and the rest were conducted exclusively in community-dwelling populations. Four studies exclusively enrolled Black participants.60,61,74,82 Three studies evaluated vitamin D2 as a 2000 IU daily dose,69 a 50 000 IU weekly dose,63 or a single 100 000 IU dose.71 The rest of the studies evaluated various daily, weekly, monthly, or single doses of vitamin D3. In the studies using daily doses, the doses ranged from as low as 400 IU to as high as 4000 IU, and the studies using weekly doses ranged from 20 000 IU to 50 000 IU. Nine studies provided calcium to both the active vitamin D treatment group and the control group.16,21,22,43,60,61,65,74,84 The rest of the included studies did not include any calcium as part of the active or control intervention. The duration of the intervention ranged from a single, 1-time dose to 3 years; however, the duration of intervention was less than 6 months in 22 of the 36 studies.

No studies specified adverse events as primary outcomes. With 1 exception,39 primary outcomes included laboratory (eg, serum vitamin D level), imaging (eg, bone mineral density), or physical strength (eg, grip strength) measures. Seven studies collected data on adverse events at study visits,16,43,65,67,72,77,86 2 used follow-up telephone calls,25,63 1 used a toll-free call-in line available to participants to report adverse events,84 and 1 used multiple methods.41 Fourteen studies did not report how adverse events were ascertained.15,17,18,35,36,58,60,68-71,73,82,88 Consistent definitions for total and serious adverse events were not used across studies.

Total Adverse Events

Twenty-four studies (n = 3938) reported overall adverse events (eTable 8 in the Supplement).15-18,25,35,41,43,58,60,63,65,67-73,77,82,84,86,88 The incidence of adverse events varied by study, ranging from 0% to 92% across the treatment and control groups. However, within any given study, the incidence of adverse events was generally similar between treatment and control groups. Seven studies reported no adverse events.15,35,60,70,71,73,82 However, 1 of the studies that reported no adverse events did in fact note adverse effects (eg, nausea) and discontinuations from the study.35 Of the 14 studies reporting total adverse events by group, only 3 conducted statistical significance testing, and all reported no significant differences between groups.18,77,86 Although many studies did not list the specific adverse events experienced by participants, those that did reported the following types of adverse events: abdominal discomfort, gastrointestinal issues, fatigue, musculoskeletal symptoms, nontoxic goiter, light-headedness, severe headaches, nausea, rash/hives, weakness, numbness, constipation, and itching.16,35,60,63,65,72,86

Serious Adverse Events

Sixteen RCTs (n = 3912) reported serious adverse events (eTable 9 in the Supplement).17,18,21,22,27,36,43,58,60,61,63,68,72,78,84,88 The incidence of serious adverse events ranged from 0% to 29.4% across the groups within the studies; the incidence appeared similar between treatment and control groups, although formal statistical significance testing was not conducted in any study. Seven studies (n = 1702) reported 0 serious adverse events overall.17,36,60,63,72,84,88 Five studies (n = 1341) reported serious adverse events, but authors indicated that these were most likely unrelated to the study medication.21,22,27,58,61

Kidney Stones

Ten RCTs (n = 2120) reported on kidney stones (eTable 11 in the Supplement).19,21,22,25,26,43,61,65,66,88 In all but 1 of those studies, the incidence of kidney stones was reported in 0% of both the active treatment and control groups. In the study reporting more than 0 events, 1 participant in the lower-dose vitamin D group (800 IU daily) reported a kidney stone; no kidney stones were reported in the placebo group or in the higher-dose vitamin D group (50 000 IU twice monthly).26 This study did not use calcium as part of the active treatment or control intervention.

Other Harms

Discontinuations due to adverse events and various other specific harms are detailed in the eResults and eTables 10 and 12 in the Supplement.

Variation in Harms by Subgroup

Data were too limited to evaluate differences in harms by subgroups of participants.

Discussion

This review is an updated report regarding screening for vitamin D deficiency in adults. However, no studies were identified that evaluated screening for vitamin D deficiency; thus, this evidence report was limited to an evaluation of the benefits and harms of vitamin D treatment among participants at risk for deficiency based on low serum vitamin D levels. Compared with the 2014 review for the USPSTF on this topic,8,9 23 new RCTs were added, and 4 RCTs were excluded. Table 2 summarizes the evidence by KQ and provides an assessment of the strength of evidence.

For benefits of treatment (KQ3) among community-dwelling populations, the strength of evidence was assessed as moderate for no benefit for mortality, any fractures, incident diabetes, cardiovascular disease, and incident cancer. For these outcomes, the strength of evidence was downgraded for study limitations or imprecision. The strength of evidence was assessed as low for no benefit for hip fractures and depression because of study limitations and imprecision. The strength of evidence for incidence of falls was assessed as low for no benefit; it was downgraded because of inconsistency between the various fall measures (incidence vs total falls) and for imprecision in effect estimates. The strength of evidence for physical functioning and infection was assessed as insufficient because of inconsistency, imprecision, and study limitations. For harms of treatment (KQ4), the strength of evidence was assessed as low for no harm for total adverse events, serious adverse events, discontinuations due to adverse events, kidney stones, and other harms. The strength of evidence was downgraded for these outcomes because of imprecision and study limitations. Although studies were consistent in demonstrating no difference in harms between active treatment and control groups, the absolute incidence of reported adverse events varied vastly across studies, likely because of different approaches to defining and ascertaining these outcomes across the studies.

Despite a reasonable number of studies reporting falls outcomes, the body of evidence demonstrated mixed findings. Among the studies reporting the incidence of 1 or more falls, a numerical but not statistically significant decrease (pooled ARD, −4.3%) was observed among community-dwelling populations. The most recent good-quality trial reported the incidence of 2 or more falls among subgroups of participants with low vitamin D levels and also found no significant association, although effect estimates were imprecise. Among the studies reporting total number of falls, a small but statistically significant decrease (−0.1 falls per person-year) in the total number of falls was observed. Estimates for both types of outcomes were inconsistent and imprecise. Some studies reported both outcomes, but others reported only 1 of these outcomes, raising the possibility of selective outcome reporting. One hypothesis to explain the difference between these 2 outcomes is that although vitamin D may not prevent a first fall, it may have some benefit in preventing repeat falls.

A related systematic review on behalf of the USPSTF recommendation for fall prevention in community-dwelling populations at increased risk of falls found mixed findings for vitamin D interventions.92 There was also evidence of possible harms from high-dose vitamin D in such populations, resulting in a recommendation against vitamin D supplementation in community-dwelling adults 65 years or older.92,93 The falls prevention review excluded studies conducted among vitamin D–deficient populations; thus, additional evidence specifically in vitamin D–deficient populations is needed to be able to draw definitive conclusions about the effect of screening for vitamin D deficiency on falls among community-dwelling adults.

Findings regarding benefits of treatment in this review are not directly comparable with those from other reviews of vitamin D supplementation because this review was focused specifically on persons with low vitamin D levels (ie, less than 20 or 30 ng/mL) and other differences in study selection criteria. Despite these differences, the findings from this review are largely consistent with those from other reviews conducted in broader populations with respect to most outcomes.

Limitations

This evidence review had several limitations. First, no available evidence that directly evaluated the health benefits and harms of screening (KQ1 and KQ2) was identified. Second, studies selected for this review included some conducted in institutionalized settings. However, the synthesis and strength of evidence assessment focused mainly on community-dwelling populations because USPSTF recommendations are for clinical preventive services in or referred from primary care settings. Studies focused on populations with a specific clinical condition to evaluate the treatment of vitamin D deficiency for the alleviation of specific symptoms or issues associated with that condition were not included. Third, the comparative benefits or harms of various vitamin D doses, formulations, or durations of treatment were not assessed. Fourth, this review included studies that enrolled participants based on 25(OH)D levels that used various assays and that may not have been standardized according to current criteria from the Vitamin D Standardization Program.94 Fifth, for the trials enrolling participants unselected with respect to vitamin D status, only findings from the vitamin D–deficient subgroups were reported. Findings from the overall population were not included, but these may be eligible to be included in the next update of a related review of vitamin D supplementation conducted on behalf of the USPSTF.95

Conclusions

No studies evaluated the direct benefit or harms of screening for vitamin D deficiency. Among asymptomatic, community-dwelling populations with low vitamin D levels, the evidence suggests that treatment with vitamin D (with or without calcium) has no effect on mortality or incidence of fractures, falls, depression, diabetes, cardiovascular disease, cancer, or adverse events. The evidence is inconclusive about the effect of treatment on physical functioning and infection.

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Article Information

Corresponding Author: Leila C. Kahwati, MD, MPH, RTI International, 3040 E Cornwallis Rd, Research Triangle Park, NC 27709 (Lkahwati@rti.org).

Accepted for Publication: December 21, 2020.

Author Contributions: Dr Kahwati had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Kahwati, LeBlanc, Palmieri Weber, Clark, Viswanathan.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Kahwati, LeBlanc, Giger, Clark, Suvada, Guisinger.

Critical revision of the manuscript for important intellectual content: Kahwati, LeBlanc, Palmieri Weber, Suvada, Viswanathan.

Statistical analysis: Kahwati, Weber, Clark, Suvada.

Obtained funding: Kahwati, Viswanathan.

Administrative, technical, or material support: Kahwati, Palmieri Weber, Giger, Clark, Suvada, Guisinger, Viswanathan.

Supervision: Kahwati.

Conflict of Interest Disclosures: None reported.

Funding/Support: This research was funded under contract HHSA-290-2015-00011-I, Task Order 11, from the Agency for Healthcare Research and Quality (AHRQ) under a contract to support the US Preventive Services Task Force (USPSTF).

Role of the Funder/Sponsor: Investigators worked with USPSTF members and AHRQ staff to develop the scope, analytic framework, and key questions for this review. AHRQ had no role in study selection, quality assessment, or synthesis. AHRQ staff provided project oversight, reviewed the report to ensure that the analysis met methodological standards, and distributed the draft for peer review. Otherwise, AHRQ had no role in the conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript findings.

Disclaimer: The opinions expressed in this document are those of the authors and do not reflect the official position of AHRQ or the US Department of Health and Human Services.

Additional Contributions: We acknowledge the following individuals for their contributions to this project: AHRQ staff Howard Tracer, MD, andTracy Wolff, MD, MPH; former AHRQ staff Quyen Ngo-Metzger, MD, MPH; current and former members of the USPSTF who contributed to topic deliberations; and RTI International–University of North Carolina Evidence-based Practice Center staff B. Lynn Whitener, DrPH, Carol Woodell, BSPH, Sharon Barrell, MA, and Loraine Monroe. USPSTF members, peer reviewers, and federal partner reviewers did not receive financial compensation for their contributions.

Additional Information: A draft version of the full evidence report underwent external peer review from 4 content experts (John Aloia, MD, New York University Winthrop Bone Mineral Research Center; JoAnn E. Manson, MD, MPH, DrPH, Harvard Medical School; Clifford Rosen, MD, Maine Medical Center Research Institute; and Christopher Sempos, PhD, Vitamin D Standardization Program LLC) and 4 individuals from 3 federal partner reviewers (2 from the National Institutes of Health, 1 from the Centers for Disease Control and Prevention). Comments from reviewers were presented to the USPSTF during its deliberation of the evidence and were considered in preparing the final evidence review.

Editorial Disclaimer: This evidence report is presented as a document in support of the accompanying USPSTF Recommendation Statement. It did not undergo additional peer review after submission to JAMA.

References
1.
Institute of Medicine.  Dietary Reference Intakes For Calcium and Vitamin D. National Academies Press; 2011.
2.
Pludowski  P, Holick  MF, Pilz  S,  et al.  Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality—a review of recent evidence.   Autoimmun Rev. 2013;12(10):976-989. doi:10.1016/j.autrev.2013.02.004PubMedGoogle ScholarCrossref
3.
Autier  P, Mullie  P, Macacu  A,  et al.  Effect of vitamin D supplementation on non-skeletal disorders: a systematic review of meta-analyses and randomised trials.   Lancet Diabetes Endocrinol. 2017;5(12):986-1004. doi:10.1016/S2213-8587(17)30357-1PubMedGoogle ScholarCrossref
4.
Sempos  CT, Heijboer  AC, Bikle  DD,  et al.  Vitamin D assays and the definition of hypovitaminosis D: results from the First International Conference on Controversies in Vitamin D.   Br J Clin Pharmacol. 2018;84(10):2194-2207. doi:10.1111/bcp.13652PubMedGoogle ScholarCrossref
5.
Ross  AC, Manson  JE, Abrams  SA,  et al.  The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know.   J Clin Endocrinol Metab. 2011;96(1):53-58. doi:10.1210/jc.2010-2704PubMedGoogle ScholarCrossref
6.
Holick  MF, Binkley  NC, Bischoff-Ferrari  HA,  et al; Endocrine Society.  Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline.   J Clin Endocrinol Metab. 2011;96(7):1911-1930. doi:10.1210/jc.2011-0385PubMedGoogle ScholarCrossref
7.
LeFevre  ML; US Preventive Services Task Force.  Screening for vitamin D deficiency in adults: U.S. Preventive Services Task Force recommendation statement.   Ann Intern Med. 2015;162(2):133-140. doi:10.7326/M14-2450PubMedGoogle ScholarCrossref
8.
LeBlanc  E, Chou  R, Zakher  B, Daeges  M, Pappas  M.  Screening for Vitamin D deficiency: Systematic Review for the U.S. Preventive Services Task Force Recommendation. US Preventive Services Task Force; 2014.
9.
LeBlanc  ES, Zakher  B, Daeges  M, Pappas  M, Chou  R.  Screening for vitamin D deficiency: a systematic review for the U.S. Preventive Services Task Force.   Ann Intern Med. 2015;162(2):109-122. doi:10.7326/M14-1659PubMedGoogle ScholarCrossref
10.
Kahwati  LC, LeBlanc  E, Weber  RP,  et al.  Screening for Vitamin D Deficiency in Adults: An Evidence Review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 201. Agency for Healthcare Research and Quality; 2021. AHRQ publication 20-05270-EF-1.
11.
 Human Development Report 2016. United Nations Development Programme; 2016.
12.
Sterne  JAC, Savović  J, Page  MJ,  et al.  RoB 2: a revised tool for assessing risk of bias in randomised trials.   BMJ. 2019;366:l4898. doi:10.1136/bmj.l4898PubMedGoogle ScholarCrossref
13.
DerSimonian  R, Laird  N.  Meta-analysis in clinical trials.   Control Clin Trials. 1986;7(3):177-188. doi:10.1016/0197-2456(86)90046-2PubMedGoogle ScholarCrossref
14.
Agency for Healthcare Research and Quality.  Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Agency for Healthcare Research and Quality; 2014. AHRQ publication 10(14)-EHC063-EF.
15.
Arvold  DS, Odean  MJ, Dornfeld  MP,  et al.  Correlation of symptoms with vitamin D deficiency and symptom response to cholecalciferol treatment: a randomized controlled trial.   Endocr Pract. 2009;15(3):203-212. doi:10.4158/EP.15.3.203PubMedGoogle ScholarCrossref
16.
Bischoff  HA, Stähelin  HB, Dick  W,  et al.  Effects of vitamin D and calcium supplementation on falls: a randomized controlled trial.   J Bone Miner Res. 2003;18(2):343-351. doi:10.1359/jbmr.2003.18.2.343PubMedGoogle ScholarCrossref
17.
Bislev  LS, Langagergaard Rødbro  L, Rolighed  L, Sikjaer  T, Rejnmark  L.  Bone microstructure in response to vitamin D3 supplementation: a randomized placebo-controlled trial.   Calcif Tissue Int. 2019;104(2):160-170. doi:10.1007/s00223-018-0481-6PubMedGoogle ScholarCrossref
18.
Brazier  M, Grados  F, Kamel  S,  et al.  Clinical and laboratory safety of one year’s use of a combination calcium + vitamin D tablet in ambulatory elderly women with vitamin D insufficiency: results of a multicenter, randomized, double-blind, placebo-controlled study.   Clin Ther. 2005;27(12):1885-1893. doi:10.1016/j.clinthera.2005.12.010PubMedGoogle ScholarCrossref
19.
Chapuy  MC, Pamphile  R, Paris  E,  et al.  Combined calcium and vitamin D3 supplementation in elderly women: confirmation of reversal of secondary hyperparathyroidism and hip fracture risk: the Decalyos II study.   Osteoporos Int. 2002;13(3):257-264. doi:10.1007/s001980200023PubMedGoogle ScholarCrossref
20.
Davidson  MB, Duran  P, Lee  ML, Friedman  TC.  High-dose vitamin D supplementation in people with prediabetes and hypovitaminosis D.   Diabetes Care. 2013;36(2):260-266. doi:10.2337/dc12-1204PubMedGoogle ScholarCrossref
21.
Gallagher  JC, Jindal  PS, Smith  LM.  Vitamin D supplementation in young white and African American women.   J Bone Miner Res. 2014;29(1):173-181. doi:10.1002/jbmr.2010PubMedGoogle ScholarCrossref
22.
Gallagher  JC, Sai  A, Templin  T  II, Smith  L.  Dose response to vitamin D supplementation in postmenopausal women: a randomized trial.   Ann Intern Med. 2012;156(6):425-437. doi:10.7326/0003-4819-156-6-201203200-00005PubMedGoogle ScholarCrossref
23.
Gallagher  JC, Peacock  M, Yalamanchili  V, Smith  LM.  Effects of vitamin D supplementation in older African American women.   J Clin Endocrinol Metab. 2013;98(3):1137-1146. doi:10.1210/jc.2012-3106PubMedGoogle ScholarCrossref
24.
Smith  LM, Gallagher  JC, Suiter  C.  Medium doses of daily vitamin D decrease falls and higher doses of daily vitamin D3 increase falls: a randomized clinical trial.   J Steroid Biochem Mol Biol. 2017;173:317-322. doi:10.1016/j.jsbmb.2017.03.015PubMedGoogle ScholarCrossref
25.
Grimnes  G, Figenschau  Y, Almås  B, Jorde  R.  Vitamin D, insulin secretion, sensitivity, and lipids: results from a case-control study and a randomized controlled trial using hyperglycemic clamp technique.   Diabetes. 2011;60(11):2748-2757. doi:10.2337/db11-0650PubMedGoogle ScholarCrossref
26.
Hansen  KE, Johnson  RE, Chambers  KR,  et al.  Treatment of vitamin D insufficiency in postmenopausal women: a randomized clinical trial.   JAMA Intern Med. 2015;175(10):1612-1621. doi:10.1001/jamainternmed.2015.3874PubMedGoogle ScholarCrossref
27.
Hin  H, Tomson  J, Newman  C,  et al.  Optimum dose of vitamin D for disease prevention in older people: BEST-D trial of vitamin D in primary care.   Osteoporos Int. 2017;28(3):841-851. doi:10.1007/s00198-016-3833-yPubMedGoogle ScholarCrossref
28.
Tomson  J, Hin  H, Emberson  J,  et al.  Effects of vitamin D on blood pressure, arterial stiffness, and cardiac function in older people after 1 year: BEST-D (Biochemical Efficacy and Safety Trial of Vitamin D).   J Am Heart Assoc. 2017;6(10):e005707. doi:10.1161/JAHA.117.005707PubMedGoogle Scholar
29.
Clarke  R, Newman  C, Tomson  J,  et al.  Estimation of the optimum dose of vitamin D for disease prevention in older people: rationale, design and baseline characteristics of the BEST-D trial.   Maturitas. 2015;80(4):426-431. doi:10.1016/j.maturitas.2015.01.013PubMedGoogle ScholarCrossref
30.
Jackson  RD, LaCroix  AZ, Gass  M,  et al; Women’s Health Initiative Investigators.  Calcium plus vitamin D supplementation and the risk of fractures.   N Engl J Med. 2006;354(7):669-683. doi:10.1056/NEJMoa055218PubMedGoogle ScholarCrossref
31.
de Boer  IH, Tinker  LF, Connelly  S,  et al; Women’s Health Initiative Investigators.  Calcium plus vitamin D supplementation and the risk of incident diabetes in the Women’s Health Initiative.   Diabetes Care. 2008;31(4):701-707. doi:10.2337/dc07-1829PubMedGoogle ScholarCrossref
32.
Wactawski-Wende  J, Kotchen  JM, Anderson  GL,  et al; Women’s Health Initiative Investigators.  Calcium plus vitamin D supplementation and the risk of colorectal cancer.   N Engl J Med. 2006;354(7):684-696. doi:10.1056/NEJMoa055222PubMedGoogle ScholarCrossref
33.
Chlebowski  RT, Johnson  KC, Kooperberg  C,  et al; Women’s Health Initiative Investigators.  Calcium plus vitamin D supplementation and the risk of breast cancer.   J Natl Cancer Inst. 2008;100(22):1581-1591. doi:10.1093/jnci/djn360PubMedGoogle ScholarCrossref
34.
LaCroix  AZ, Kotchen  J, Anderson  G,  et al.  Calcium plus vitamin D supplementation and mortality in postmenopausal women: the Women’s Health Initiative calcium–vitamin D randomized controlled trial.   J Gerontol A Biol Sci Med Sci. 2009;64(5):559-567. doi:10.1093/gerona/glp006PubMedGoogle ScholarCrossref
35.
Janssen  HCJP, Samson  MM, Verhaar  HJJ.  Muscle strength and mobility in vitamin D–insufficient female geriatric patients: a randomized controlled trial on vitamin D and calcium supplementation.   Aging Clin Exp Res. 2010;22(1):78-84. doi:10.1007/BF03324819PubMedGoogle ScholarCrossref
36.
Jorde  R, Kubiak  J.  No improvement in depressive symptoms by vitamin D supplementation: results from a randomised controlled trial.   J Nutr Sci. 2018;7:e30. doi:10.1017/jns.2018.19PubMedGoogle Scholar
37.
Jorde  R, Sollid  ST, Svartberg  J,  et al.  Vitamin D 20,000 IU per week for five years does not prevent progression from prediabetes to diabetes.   J Clin Endocrinol Metab. 2016;101(4):1647-1655. doi:10.1210/jc.2015-4013PubMedGoogle ScholarCrossref
38.
Jorde  R, Sollid  ST, Svartberg  J, Joakimsen  RM, Grimnes  G, Hutchinson  MY.  Prevention of urinary tract infections with vitamin D supplementation 20,000 IU per week for five years: results from an RCT including 511 subjects.   Infect Dis (Lond). 2016;48(11-12):823-828. doi:10.1080/23744235.2016.1201853PubMedGoogle ScholarCrossref
39.
Kärkkäinen  MK, Tuppurainen  M, Salovaara  K,  et al.  Does daily vitamin D 800 IU and calcium 1000 mg supplementation decrease the risk of falling in ambulatory women aged 65-71 years? a 3-year randomized population-based trial (OSTPRE-FPS).   Maturitas. 2010;65(4):359-365. doi:10.1016/j.maturitas.2009.12.018PubMedGoogle ScholarCrossref
40.
Kärkkäinen  M, Tuppurainen  M, Salovaara  K,  et al.  Effect of calcium and vitamin D supplementation on bone mineral density in women aged 65-71 years: a 3-year randomized population-based trial (OSTPRE-FPS).   Osteoporos Int. 2010;21(12):2047-2055. doi:10.1007/s00198-009-1167-8PubMedGoogle ScholarCrossref
41.
Kjaergaard  M, Waterloo  K, Wang  CE,  et al.  Effect of vitamin D supplement on depression scores in people with low levels of serum 25-hydroxyvitamin D: nested case-control study and randomised clinical trial.   Br J Psychiatry. 2012;201(5):360-368. doi:10.1192/bjp.bp.111.104349PubMedGoogle ScholarCrossref
42.
Krieg  MA, Jacquet  AF, Bremgartner  M, Cuttelod  S, Thiébaud  D, Burckhardt  P.  Effect of supplementation with vitamin D3 and calcium on quantitative ultrasound of bone in elderly institutionalized women: a longitudinal study.   Osteoporos Int. 1999;9(6):483-488.PubMedGoogle Scholar
43.
Lips  P, Binkley  N, Pfeifer  M,  et al.  Once-weekly dose of 8400 IU vitamin D(3) compared with placebo: effects on neuromuscular function and tolerability in older adults with vitamin D insufficiency.   Am J Clin Nutr. 2010;91(4):985-991. doi:10.3945/ajcn.2009.28113PubMedGoogle ScholarCrossref
44.
Lips  P, Graafmans  WC, Ooms  ME, Bezemer  PD, Bouter  LM.  Vitamin D supplementation and fracture incidence in elderly persons: a randomized, placebo-controlled clinical trial.   Ann Intern Med. 1996;124(4):400-406. doi:10.7326/0003-4819-124-4-199602150-00003PubMedGoogle ScholarCrossref
45.
Ooms  ME, Roos  JC, Bezemer  PD, van der Vijgh  WJ, Bouter  LM, Lips  P.  Prevention of bone loss by vitamin D supplementation in elderly women: a randomized double-blind trial.   J Clin Endocrinol Metab. 1995;80(4):1052-1058.PubMedGoogle Scholar
46.
Manson  JE, Cook  NR, Lee  IM,  et al; VITAL Research Group.  Vitamin D supplements and prevention of cancer and cardiovascular disease.   N Engl J Med. 2019;380(1):33-44. doi:10.1056/NEJMoa1809944PubMedGoogle ScholarCrossref
47.
Manson  JE, Cook  NR, Lee  IM,  et al; VITAL Research Group.  Marine n-3 fatty acids and prevention of cardiovascular disease and cancer.   N Engl J Med. 2019;380(1):23-32. doi:10.1056/NEJMoa1811403PubMedGoogle ScholarCrossref
48.
Manson  JE, Bassuk  SS, Lee  IM,  et al.  The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease.   Contemp Clin Trials. 2012;33(1):159-171. doi:10.1016/j.cct.2011.09.009PubMedGoogle ScholarCrossref
49.
Donlon  CM, LeBoff  MS, Chou  SH,  et al.  Baseline characteristics of participants in the VITamin D and OmegA-3 TriaL (VITAL): effects on bone structure and architecture.   Contemp Clin Trials. 2018;67:56-67. doi:10.1016/j.cct.2018.02.003PubMedGoogle ScholarCrossref
50.
Bassuk  SS, Manson  JE, Lee  IM,  et al.  Baseline characteristics of participants in the VITamin D and OmegA-3 TriaL (VITAL).   Contemp Clin Trials. 2016;47:235-243. doi:10.1016/j.cct.2015.12.022PubMedGoogle ScholarCrossref
51.
Pfeifer  M, Begerow  B, Minne  HW, Suppan  K, Fahrleitner-Pammer  A, Dobnig  H.  Effects of a long-term vitamin D and calcium supplementation on falls and parameters of muscle function in community-dwelling older individuals.   Osteoporos Int. 2009;20(2):315-322. doi:10.1007/s00198-008-0662-7PubMedGoogle ScholarCrossref
52.
Pfeifer  M, Begerow  B, Minne  HW, Abrams  C, Nachtigall  D, Hansen  C.  Effects of a short-term vitamin D and calcium supplementation on body sway and secondary hyperparathyroidism in elderly women.   J Bone Miner Res. 2000;15(6):1113-1118. doi:10.1359/jbmr.2000.15.6.1113PubMedGoogle ScholarCrossref
53.
Pittas  AG, Dawson-Hughes  B, Sheehan  P,  et al; D2d Research Group.  Vitamin D supplementation and prevention of type 2 diabetes.   N Engl J Med. 2019;381(6):520-530. doi:10.1056/NEJMoa1900906PubMedGoogle ScholarCrossref
54.
Khaw  KT, Stewart  AW, Waayer  D,  et al.  Effect of monthly high-dose vitamin D supplementation on falls and non-vertebral fractures: secondary and post-hoc outcomes from the randomised, double-blind, placebo-controlled ViDA trial.   Lancet Diabetes Endocrinol. 2017;5(6):438-447. doi:10.1016/S2213-8587(17)30103-1PubMedGoogle ScholarCrossref
55.
Scragg  R, Stewart  AW, Waayer  D,  et al.  Effect of monthly high-dose vitamin D supplementation on cardiovascular disease in the Vitamin D Assessment Study: a randomized clinical trial.   JAMA Cardiol. 2017;2(6):608-616. doi:10.1001/jamacardio.2017.0175PubMedGoogle ScholarCrossref
56.
Sluyter  JD, Camargo  CA  Jr, Stewart  AW,  et al.  Effect of monthly, high-dose, long-term vitamin D supplementation on central blood pressure parameters: a randomized controlled trial substudy.   J Am Heart Assoc. 2017;6(10):e006802. doi:10.1161/JAHA.117.006802PubMedGoogle Scholar
57.
Shea  MK, Fielding  RA, Dawson-Hughes  B.  The effect of vitamin D supplementation on lower-extremity power and function in older adults: a randomized controlled trial.   Am J Clin Nutr. 2019;109(2):369-379. doi:10.1093/ajcn/nqy290PubMedGoogle ScholarCrossref
58.
Wood  AD, Secombes  KR, Thies  F,  et al.  Vitamin D3 supplementation has no effect on conventional cardiovascular risk factors: a parallel-group, double-blind, placebo-controlled RCT.   J Clin Endocrinol Metab. 2012;97(10):3557-3568. doi:10.1210/jc.2012-2126PubMedGoogle ScholarCrossref
59.
Macdonald  HM, Gryka  A, Tang  JCY, Aucott  LS, Fraser  WD, Wood  AD.  Longevity of daily oral vitamin D3 supplementation: differences in 25OHD and 24,25(OH)2D observed 2 years after cessation of a 1-year randomised controlled trial (VICtORy RECALL).   Osteoporos Int. 2017;28(12):3361-3372. doi:10.1007/s00198-017-4201-2PubMedGoogle ScholarCrossref
60.
Aloia  J, Fazzari  M, Islam  S,  et al.  Vitamin D supplementation in elderly Black women does not prevent bone loss: a randomized controlled trial.   J Bone Miner Res. 2018;33(11):1916-1922. doi:10.1002/jbmr.3521PubMedGoogle ScholarCrossref
61.
Aloia  JF, Talwar  SA, Pollack  S, Yeh  J.  A randomized controlled trial of vitamin D3 supplementation in African American women.   Arch Intern Med. 2005;165(14):1618-1623. doi:10.1001/archinte.165.14.1618PubMedGoogle ScholarCrossref
62.
Talwar  SA, Aloia  JF, Pollack  S, Yeh  JK.  Dose response to vitamin D supplementation among postmenopausal African American women.   Am J Clin Nutr. 2007;86(6):1657-1662. doi:10.1093/ajcn/86.5.1657PubMedGoogle ScholarCrossref
63.
Borgi  L, McMullan  C, Wohlhueter  A, Curhan  GC, Fisher  ND, Forman  JP.  Effect of vitamin D on endothelial function: a randomized, double-blind, placebo-controlled trial.   Am J Hypertens. 2017;30(2):124-129. doi:10.1093/ajh/hpw135PubMedGoogle ScholarCrossref
64.
McMullan  CJ, Borgi  L, Curhan  GC, Fisher  N, Forman  JP.  The effect of vitamin D on renin-angiotensin system activation and blood pressure: a randomized control trial.   J Hypertens. 2017;35(4):822-829. doi:10.1097/HJH.0000000000001220PubMedGoogle ScholarCrossref
65.
Gagnon  C, Daly  RM, Carpentier  A,  et al.  Effects of combined calcium and vitamin D supplementation on insulin secretion, insulin sensitivity and β-cell function in multi-ethnic vitamin D–deficient adults at risk for type 2 diabetes: a pilot randomized, placebo-controlled trial.   PLoS One. 2014;9(10):e109607. doi:10.1371/journal.pone.0109607PubMedGoogle Scholar
66.
Honkanen  R, Alhava  E, Parviainen  M, Talasniemi  S, Mönkkönen  R.  The necessity and safety of calcium and vitamin D in the elderly.   J Am Geriatr Soc. 1990;38(8):862-866. doi:10.1111/j.1532-5415.1990.tb05700.xPubMedGoogle ScholarCrossref
67.
Kearns  MD, Binongo  JN, Watson  D,  et al.  The effect of a single, large bolus of vitamin D in healthy adults over the winter and following year: a randomized, double-blind, placebo-controlled trial.   Eur J Clin Nutr. 2015;69(2):193-197. doi:10.1038/ejcn.2014.209PubMedGoogle ScholarCrossref
68.
Knutsen  KV, Madar  AA, Lagerløv  P,  et al.  Does vitamin D improve muscle strength in adults? a randomized, double-blind, placebo-controlled trial among ethnic minorities in Norway.   J Clin Endocrinol Metab. 2014;99(1):194-202. doi:10.1210/jc.2013-2647PubMedGoogle ScholarCrossref
69.
Lehmann  U, Hirche  F, Stangl  GI, Hinz  K, Westphal  S, Dierkes  J.  Bioavailability of vitamin D(2) and D(3) in healthy volunteers, a randomized placebo-controlled trial.   J Clin Endocrinol Metab. 2013;98(11):4339-4345. doi:10.1210/jc.2012-4287PubMedGoogle ScholarCrossref
70.
Lerchbaum  E, Pilz  S, Trummer  C,  et al.  Vitamin D and testosterone in healthy men: a randomized controlled trial.   J Clin Endocrinol Metab. 2017;102(11):4292-4302. doi:10.1210/jc.2017-01428PubMedGoogle ScholarCrossref
71.
Martineau  AR, Wilkinson  RJ, Wilkinson  KA,  et al.  A single dose of vitamin D enhances immunity to mycobacteria.   Am J Respir Crit Care Med. 2007;176(2):208-213. doi:10.1164/rccm.200701-007OCPubMedGoogle ScholarCrossref
72.
Mason  C, Xiao  L, Imayama  I,  et al.  Vitamin D3 supplementation during weight loss: a double-blind randomized controlled trial.   Am J Clin Nutr. 2014;99(5):1015-1025. doi:10.3945/ajcn.113.073734PubMedGoogle ScholarCrossref
73.
Moreira-Lucas  TS, Duncan  AM, Rabasa-Lhoret  R,  et al.  Effect of vitamin D supplementation on oral glucose tolerance in individuals with low vitamin D status and increased risk for developing type 2 diabetes (EVIDENCE): a double-blind, randomized, placebo-controlled clinical trial.   Diabetes Obes Metab. 2017;19(1):133-141. doi:10.1111/dom.12794PubMedGoogle ScholarCrossref
74.
Ng  K, Scott  JB, Drake  BF,  et al.  Dose response to vitamin D supplementation in African Americans: results of a 4-arm, randomized, placebo-controlled trial.   Am J Clin Nutr. 2014;99(3):587-598. doi:10.3945/ajcn.113.067777PubMedGoogle ScholarCrossref
75.
Chandler  PD, Giovannucci  EL, Scott  JB,  et al.  Null association between vitamin D and PSA levels among black men in a vitamin D supplementation trial.   Cancer Epidemiol Biomarkers Prev. 2014;23(9):1944-1947. doi:10.1158/1055-9965.EPI-14-0522PubMedGoogle ScholarCrossref
76.
Chandler  PD, Scott  JB, Drake  BF,  et al.  Impact of vitamin D supplementation on inflammatory markers in African Americans: results of a four-arm, randomized, placebo-controlled trial.   Cancer Prev Res (Phila). 2014;7(2):218-225. doi:10.1158/1940-6207.CAPR-13-0338-TPubMedGoogle ScholarCrossref
77.
Nowak  A, Boesch  L, Andres  E,  et al.  Effect of vitamin D3 on self-perceived fatigue: a double-blind randomized placebo-controlled trial.   Medicine (Baltimore). 2016;95(52):e5353. doi:10.1097/MD.0000000000005353PubMedGoogle Scholar
78.
Pilz  S, Gaksch  M, Kienreich  K,  et al.  Effects of vitamin D on blood pressure and cardiovascular risk factors: a randomized controlled trial.   Hypertension. 2015;65(6):1195-1201. doi:10.1161/HYPERTENSIONAHA.115.05319PubMedGoogle ScholarCrossref
79.
Grübler  MR, Gaksch  M, Kienreich  K,  et al.  Effects of vitamin D supplementation on glycated haemoglobin and fasting glucose levels in hypertensive patients: a randomized controlled trial.   Diabetes Obes Metab. 2016;18(10):1006-1012. doi:10.1111/dom.12709PubMedGoogle ScholarCrossref
80.
Grübler  MR, Gaksch  M, Kienreich  K,  et al.  Effects of vitamin D supplementation on plasma aldosterone and renin—a randomized placebo-controlled trial.   J Clin Hypertens (Greenwich). 2016;18(7):608-613. doi:10.1111/jch.12825PubMedGoogle ScholarCrossref
81.
Grübler  MR, Gaksch  M, Kienreich  K,  et al.  Effects of vitamin D3 on asymmetric- and symmetric dimethylarginine in arterial hypertension.   J Steroid Biochem Mol Biol. 2018;175:157-163. doi:10.1016/j.jsbmb.2016.12.014PubMedGoogle ScholarCrossref
82.
Raed  A, Bhagatwala  J, Zhu  H,  et al.  Dose responses of vitamin D3 supplementation on arterial stiffness in overweight African Americans with vitamin D deficiency: a placebo controlled randomized trial.   PLoS One. 2017;12(12):e0188424. doi:10.1371/journal.pone.0188424PubMedGoogle Scholar
83.
Bhagatwala  J, Zhu  H, Parikh  SJ,  et al.  Dose and time responses of vitamin D biomarkers to monthly vitamin D3 supplementation in overweight/obese African Americans with suboptimal vitamin D status: a placebo controlled randomized clinical trial.   BMC Obes. 2015;2:27. doi:10.1186/s40608-015-0056-2PubMedGoogle ScholarCrossref
84.
Tran  B, Armstrong  BK, Ebeling  PR,  et al.  Effect of vitamin D supplementation on antibiotic use: a randomized controlled trial.   Am J Clin Nutr. 2014;99(1):156-161. doi:10.3945/ajcn.113.063271PubMedGoogle ScholarCrossref
85.
Tran  B, Armstrong  BK, Carlin  JB,  et al.  Recruitment and results of a pilot trial of vitamin D supplementation in the general population of Australia.   J Clin Endocrinol Metab. 2012;97(12):4473-4480. doi:10.1210/jc.2012-2682PubMedGoogle ScholarCrossref
86.
Wamberg  L, Kampmann  U, Stødkilde-Jørgensen  H, Rejnmark  L, Pedersen  SB, Richelsen  B.  Effects of vitamin D supplementation on body fat accumulation, inflammation, and metabolic risk factors in obese adults with low vitamin D levels—results from a randomized trial.   Eur J Intern Med. 2013;24(7):644-649. doi:10.1016/j.ejim.2013.03.005PubMedGoogle ScholarCrossref
87.
Wamberg  L, Pedersen  SB, Richelsen  B, Rejnmark  L.  The effect of high-dose vitamin D supplementation on calciotropic hormones and bone mineral density in obese subjects with low levels of circulating 25-hydroxyvitamin D: results from a randomized controlled study.   Calcif Tissue Int. 2013;93(1):69-77. doi:10.1007/s00223-013-9729-3PubMedGoogle ScholarCrossref
88.
Witham  MD, Adams  F, Kabir  G, Kennedy  G, Belch  JJ, Khan  F.  Effect of short-term vitamin D supplementation on markers of vascular health in South Asian women living in the UK—a randomised controlled trial.   Atherosclerosis. 2013;230(2):293-299. doi:10.1016/j.atherosclerosis.2013.08.005PubMedGoogle ScholarCrossref
89.
LeBoff  MS, Murata  EM, Cook  NR,  et al.  VITamin D and OmegA-3 TriaL (VITAL): effects of vitamin D supplements on risk of falls in the US population.   J Clin Endocrinol Metab. 2020;105(9):2929-2938. doi:10.1210/clinem/dgaa311PubMedGoogle ScholarCrossref
90.
Scragg  R, Khaw  KT, Toop  L,  et al.  Monthly high-dose vitamin D supplementation and cancer risk: a post hoc analysis of the Vitamin D Assessment randomized clinical trial.   JAMA Oncol. 2018;4(11):e182178. doi:10.1001/jamaoncol.2018.2178PubMedGoogle Scholar
91.
Okereke  OI, Reynolds  CF  III, Mischoulon  D,  et al.  Effect of long-term vitamin D3 supplementation vs placebo on risk of depression or clinically relevant depressive symptoms and on change in mood scores: a randomized clinical trial.   JAMA. 2020;324(5):471-480. doi:10.1001/jama.2020.10224PubMedGoogle ScholarCrossref
92.
Guirguis-Blake  JM, Michael  YL, Perdue  LA, Coppola  EL, Beil  TL.  Interventions to prevent falls in older adults: updated evidence report and systematic review for the US Preventive Services Task Force.   JAMA. 2018;319(16):1705-1716. doi:10.1001/jama.2017.21962PubMedGoogle ScholarCrossref
93.
Grossman  DC, Curry  SJ, Owens  DK,  et al; US Preventive Services Task Force.  Interventions to prevent falls in community-dwelling older adults: US Preventive Services Task Force recommendation statement.   JAMA. 2018;319(16):1696-1704. doi:10.1001/jama.2018.3097PubMedGoogle ScholarCrossref
94.
Atef  SH.  Vitamin D assays in clinical laboratory: past, present and future challenges.   J Steroid Biochem Mol Biol. 2018;175:136-137. doi:10.1016/j.jsbmb.2017.02.011PubMedGoogle ScholarCrossref
95.
Kahwati  LC, Weber  RP, Pan  H,  et al.  Vitamin D, calcium, or combined supplementation for the primary prevention of fractures in community-dwelling adults: evidence report and systematic review for the US Preventive Services Task Force.   JAMA. 2018;319(15):1600-1612. doi:10.1001/jama.2017.21640PubMedGoogle ScholarCrossref
96.
Guyatt  GH, Oxman  AD, Kunz  R,  et al.  GRADE guidelines 6: rating the quality of evidence—imprecision.   J Clin Epidemiol. 2011;64(12):1283-1293. doi:10.1016/j.jclinepi.2011.01.012PubMedGoogle ScholarCrossref
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