[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 18.207.240.35. Please contact the publisher to request reinstatement.
[Skip to Content Landing]
1.
Sambrook  P, Cooper  C.  Osteoporosis.  Lancet. 2006;367(9527):2010-2018. doi:10.1016/S0140-6736(06)68891-0PubMedGoogle ScholarCrossref
2.
Watts  NB, Manson  JE.  Osteoporosis and fracture risk evaluation and management: shared decision making in clinical practice.  JAMA. 2017;317(3):253-254. doi:10.1001/jama.2016.19087PubMedGoogle ScholarCrossref
3.
Wang  Y, Tao  Y, Hyman  ME, Li  J, Chen  Y.  Osteoporosis in China.  Osteoporos Int. 2009;20(10):1651-1662. doi:10.1007/s00198-009-0925-yPubMedGoogle ScholarCrossref
4.
Lund  CA, Møller  AM, Wetterslev  J, Lundstrøm  LH.  Organizational factors and long-term mortality after hip fracture surgery: a cohort study of 6143 consecutive patients undergoing hip fracture surgery.  PLoS One. 2014;9(6):e99308. doi:10.1371/journal.pone.0099308PubMedGoogle Scholar
5.
Curtis  EM, van der Velde  R, Moon  RJ,  et al.  Epidemiology of fractures in the United Kingdom, 1988-2012: variation with age, sex, geography, ethnicity and socioeconomic status.  Bone. 2016;87:19-26. doi:10.1016/j.bone.2016.03.006PubMedGoogle ScholarCrossref
6.
Holick  MF.  Vitamin D deficiency.  N Engl J Med. 2007;357(3):266-281. doi:10.1056/NEJMra070553PubMedGoogle ScholarCrossref
7.
Yao  P, Sun  L, Lu  L,  et al.  Effects of genetic and nongenetic factors on total and bioavailable 25(OH)D responses to vitamin D supplementation.  J Clin Endocrinol Metab. 2017;102(1):100-110.PubMedGoogle Scholar
8.
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
9.
Yao  P, Lu  L, Hu  Y,  et al.  A dose-response study of vitamin D3 supplementation in healthy Chinese: a 5-arm randomized, placebo-controlled trial.  Eur J Nutr. 2016;55(1):383-392. doi:10.1007/s00394-015-0859-4PubMedGoogle ScholarCrossref
10.
Feng  Y, Cheng  G, Wang  H, Chen  B.  The associations between serum 25-hydroxyvitamin D level and the risk of total fracture and hip fracture.  Osteoporos Int. 2017;28(5):1641-1652. doi:10.1007/s00198-017-3955-xPubMedGoogle ScholarCrossref
11.
Trajanoska  K, Morris  JA, Oei  L,  et al; GEFOS/GENOMOS Consortium and the 23andMe Research Team.  Assessment of the genetic and clinical determinants of fracture risk: genome wide association and mendelian randomisation study.  BMJ. 2018;362:k3225. doi:10.1136/bmj.k3225PubMedGoogle ScholarCrossref
12.
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
13.
Grossman  DC, Curry  SJ, Owens  DK,  et al; US Preventive Services Task Force.  Vitamin D, calcium, or combined supplementation for the primary prevention of fractures in community-dwelling adults: US Preventive Services Task Force recommendation statement.  JAMA. 2018;319(15):1592-1599. doi:10.1001/jama.2018.3185PubMedGoogle ScholarCrossref
14.
DIPART (Vitamin D Individual Patient Analysis of Randomized Trials) Group.  Patient level pooled analysis of 68 500 patients from seven major vitamin D fracture trials in US and Europe.  BMJ. 2010;340:b5463. doi:10.1136/bmj.b5463PubMedGoogle ScholarCrossref
15.
Bischoff-Ferrari  HA, Willett  WC, Orav  EJ,  et al.  A pooled analysis of vitamin D dose requirements for fracture prevention.  N Engl J Med. 2012;367(1):40-49. doi:10.1056/NEJMoa1109617PubMedGoogle ScholarCrossref
16.
Avenell  A, Mak  JC, O’Connell  D.  Vitamin D and vitamin D analogues for preventing fractures in post-menopausal women and older men.  Cochrane Database Syst Rev. 2014;(4):CD000227. doi:10.1002/14651858.CD000227.pub4PubMedGoogle Scholar
17.
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
18.
Zhao  JG, Zeng  XT, Wang  J, Liu  L.  Association between calcium or vitamin D supplementation and fracture incidence in community-dwelling older adults: a systematic review and meta-analysis.  JAMA. 2017;318(24):2466-2482. doi:10.1001/jama.2017.19344PubMedGoogle ScholarCrossref
19.
Bolland  MJ, Grey  A, Avenell  A.  Effects of vitamin D supplementation on musculoskeletal health: a systematic review, meta-analysis, and trial sequential analysis.  Lancet Diabetes Endocrinol. 2018;6(11):847-858. doi:10.1016/S2213-8587(18)30265-1PubMedGoogle ScholarCrossref
20.
Moher  D, Liberati  A, Tetzlaff  J, Altman  DG; PRISMA Group.  Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.  BMJ. 2009;339:b2535. doi:10.1136/bmj.b2535PubMedGoogle ScholarCrossref
21.
Sterne  JA, Hernán  MA, Reeves  BC,  et al.  ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions.  BMJ. 2016;355:i4919.PubMedGoogle ScholarCrossref
22.
Greenland  S, Longnecker  MP.  Methods for trend estimation from summarized dose-response data, with applications to meta-analysis.  Am J Epidemiol. 1992;135(11):1301-1309. doi:10.1093/oxfordjournals.aje.a116237PubMedGoogle ScholarCrossref
23.
Higgins  JPT, Altman  DG, Gøtzsche  PC,  et al; Cochrane Bias Methods Group; Cochrane Statistical Methods Group.  The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials.  BMJ. 2011;343:d5928. doi:10.1136/bmj.d5928PubMedGoogle ScholarCrossref
24.
Aung  T, Halsey  J, Kromhout  D,  et al; Omega-3 Treatment Trialists’ Collaboration.  Associations of omega-3 fatty acid supplement use with cardiovascular disease risks: meta-analysis of 10 trials involving 77 917 individuals.  JAMA Cardiol. 2018;3(3):225-234. doi:10.1001/jamacardio.2017.5205PubMedGoogle ScholarCrossref
25.
Baigent  C, Peto  R, Gray  R, Parish  S, Collins  R. Large-scale randomized evidence: trials and meta-analyses of trials. In: Warrell  DA, Cox  TM, Firth  JD, eds.  Oxford Textbook of Medicine. 5th ed. Oxford, UK: Oxford University Press; 2010:31-45. doi:10.1093/med/9780199204854.003.020303_update_002
26.
Yusuf  S, Peto  R, Lewis  J, Collins  R, Sleight  P.  Beta blockade during and after myocardial infarction: an overview of the randomized trials.  Prog Cardiovasc Dis. 1985;27(5):335-371. doi:10.1016/S0033-0620(85)80003-7PubMedGoogle ScholarCrossref
27.
Sterne  JAC, Sutton  AJ, Ioannidis  JPA,  et al.  Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials.  BMJ. 2011;343:d4002. doi:10.1136/bmj.d4002PubMedGoogle ScholarCrossref
28.
Looker  AC.  Serum 25-hydroxyvitamin D and risk of major osteoporotic fractures in older U.S. adults.  J Bone Miner Res. 2013;28(5):997-1006. doi:10.1002/jbmr.1828PubMedGoogle ScholarCrossref
29.
Buchebner  D, McGuigan  F, Gerdhem  P, Malm  J, Ridderstråle  M, Akesson  K.  Vitamin D insufficiency over 5 years is associated with increased fracture risk: an observational cohort study of elderly women.  Osteoporos Int. 2014;25(12):2767-2775. doi:10.1007/s00198-014-2823-1PubMedGoogle ScholarCrossref
30.
Barbour  KE, Houston  DK, Cummings  SR,  et al; Health ABC Study.  Calciotropic hormones and the risk of hip and nonspine fractures in older adults: the Health ABC Study.  J Bone Miner Res. 2012;27(5):1177-1185. doi:10.1002/jbmr.1545PubMedGoogle ScholarCrossref
31.
Robinson-Cohen  C, Katz  R, Hoofnagle  AN,  et al.  Mineral metabolism markers and the long-term risk of hip fracture: the cardiovascular health study.  J Clin Endocrinol Metab. 2011;96(7):2186-2193. doi:10.1210/jc.2010-2878PubMedGoogle ScholarCrossref
32.
Holvik  K, Ahmed  LA, Forsmo  S,  et al.  Low serum levels of 25-hydroxyvitamin D predict hip fracture in the elderly: a NOREPOS study.  J Clin Endocrinol Metab. 2013;98(8):3341-3350. doi:10.1210/jc.2013-1468PubMedGoogle ScholarCrossref
33.
Steingrimsdottir  L, Halldorsson  TI, Siggeirsdottir  K,  et al.  Hip fractures and bone mineral density in the elderly: importance of serum 25-hydroxyvitamin D.  PLoS One. 2014;9(3):e91122. doi:10.1371/journal.pone.0091122PubMedGoogle Scholar
34.
Cauley  JA, Danielson  ME, Boudreau  R,  et al.  Serum 25-hydroxyvitamin D and clinical fracture risk in a multiethnic cohort of women: the Women’s Health Initiative (WHI).  J Bone Miner Res. 2011;26(10):2378-2388. doi:10.1002/jbmr.449PubMedGoogle ScholarCrossref
35.
Cauley  JA, Lacroix  AZ, Wu  L,  et al.  Serum 25-hydroxyvitamin D concentrations and risk for hip fractures.  Ann Intern Med. 2008;149(4):242-250. doi:10.7326/0003-4819-149-4-200808190-00005PubMedGoogle ScholarCrossref
36.
Swanson  CM, Srikanth  P, Lee  CG,  et al; Osteoporotic Fractures in Men MrOS Study Research Group.  Associations of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D with bone mineral density, bone mineral density change, and incident nonvertebral fracture.  J Bone Miner Res. 2015;30(8):1403-1413. doi:10.1002/jbmr.2487PubMedGoogle ScholarCrossref
37.
Roddam  AW, Neale  R, Appleby  P, Allen  NE, Tipper  S, Key  TJ.  Association between plasma 25-hydroxyvitamin D levels and fracture risk: the EPIC-Oxford study.  Am J Epidemiol. 2007;166(11):1327-1336. doi:10.1093/aje/kwm210PubMedGoogle ScholarCrossref
38.
Julian  C, Lentjes  MA, Huybrechts  I,  et al.  Fracture risk in relation to serum 25-hydroxyvitamin D and physical activity: results from the EPIC-Norfolk cohort study.  PLoS One. 2016;11(10):e0164160. doi:10.1371/journal.pone.0164160PubMedGoogle Scholar
39.
Glendenning  P, Zhu  K, Inderjeeth  C, Howat  P, Lewis  JR, Prince  RL.  Effects of three-monthly oral 150,000 IU cholecalciferol supplementation on falls, mobility, and muscle strength in older postmenopausal women: a randomized controlled trial.  J Bone Miner Res. 2012;27(1):170-176. doi:10.1002/jbmr.524PubMedGoogle ScholarCrossref
40.
Larsen  AU, Grimnes  G, Jorde  R.  The effect of high-dose vitamin D3 supplementation on bone mineral density in subjects with prediabetes.  Osteoporos Int. 2018;29(1):171-180. doi:10.1007/s00198-017-4222-xPubMedGoogle ScholarCrossref
41.
Law  M, Withers  H, Morris  J, Anderson  F.  Vitamin D supplementation and the prevention of fractures and falls: results of a randomised trial in elderly people in residential accommodation.  Age Ageing. 2006;35(5):482-486. doi:10.1093/ageing/afj080PubMedGoogle ScholarCrossref
42.
Meyer  HE, Smedshaug  GB, Kvaavik  E, Falch  JA, Tverdal  A, Pedersen  JI.  Can vitamin D supplementation reduce the risk of fracture in the elderly? a randomized controlled trial.  J Bone Miner Res. 2002;17(4):709-715. doi:10.1359/jbmr.2002.17.4.709PubMedGoogle ScholarCrossref
43.
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
44.
Trivedi  DP, Doll  R, Khaw  KT.  Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial.  BMJ. 2003;326(7387):469. doi:10.1136/bmj.326.7387.469PubMedGoogle ScholarCrossref
45.
Sanders  KM, Stuart  AL, Williamson  EJ,  et al.  Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial.  JAMA. 2010;303(18):1815-1822. doi:10.1001/jama.2010.594PubMedGoogle ScholarCrossref
46.
Khaw  K-T, 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
47.
Grant  AM, Avenell  A, Campbell  MK,  et al; RECORD Trial Group.  Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial.  Lancet. 2005;365(9471):1621-1628. doi:10.1016/S0140-6736(05)63013-9PubMedGoogle ScholarCrossref
48.
Lyons  RA, Johansen  A, Brophy  S,  et al.  Preventing fractures among older people living in institutional care: a pragmatic randomised double blind placebo controlled trial of vitamin D supplementation.  Osteoporos Int. 2007;18(6):811-818. doi:10.1007/s00198-006-0309-5PubMedGoogle ScholarCrossref
49.
Smith  H, Anderson  F, Raphael  H, Maslin  P, Crozier  S, Cooper  C.  Effect of annual intramuscular vitamin D on fracture risk in elderly men and women: a population-based, randomized, double-blind, placebo-controlled trial.  Rheumatology (Oxford). 2007;46(12):1852-1857. doi:10.1093/rheumatology/kem240PubMedGoogle ScholarCrossref
50.
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
51.
Porthouse  J, Cockayne  S, King  C,  et al.  Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care.  BMJ. 2005;330(7498):1003. doi:10.1136/bmj.330.7498.1003PubMedGoogle ScholarCrossref
52.
Salovaara  K, Tuppurainen  M, Kärkkäinen  M,  et al.  Effect of vitamin D(3) and calcium on fracture risk in 65- to 71-year-old women: a population-based 3-year randomized, controlled trial: the OSTPRE-FPS.  J Bone Miner Res. 2010;25(7):1487-1495. doi:10.1002/jbmr.48PubMedGoogle ScholarCrossref
53.
Chapuy  MC, Arlot  ME, Duboeuf  F,  et al.  Vitamin D3 and calcium to prevent hip fractures in elderly women.  N Engl J Med. 1992;327(23):1637-1642. doi:10.1056/NEJM199212033272305PubMedGoogle ScholarCrossref
54.
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
55.
LeBoff  MS, Yue  AY, Copeland  T, Cook  NR, Buring  JE, Manson  JE.  VITAL-Bone Health: rationale and design of two ancillary studies evaluating the effects of vitamin D and/or omega-3 fatty acid supplements on incident fractures and bone health outcomes in the VITamin D and OmegA-3 TriaL (VITAL).  Contemp Clin Trials. 2015;41:259-268. doi:10.1016/j.cct.2015.01.007PubMedGoogle ScholarCrossref
56.
Neale  RE, Armstrong  BK, Baxter  C,  et al.  The D-Health Trial: a randomized trial of vitamin D for prevention of mortality and cancer.  Contemp Clin Trials. 2016;48:83-90. doi:10.1016/j.cct.2016.04.005PubMedGoogle ScholarCrossref
57.
Joseph  P, Pais  P, Dans  AL,  et al; TIPS-3 Investigators.  The International Polycap Study-3 (TIPS-3): Design, baseline characteristics and challenges in conduct.  Am Heart J. 2018;206:72-79. doi:10.1016/j.ahj.2018.07.012PubMedGoogle ScholarCrossref
58.
ClinicalTrials.gov. Finnish Vitamin D Trial (FIND). https://clinicaltrials.gov/ct2/show/NCT01463813. Accessed April 1, 2019.
59.
LeBlanc  ES, Pratley  RE, Dawson-Hughes  B,  et al; D2d Research Group.  Baseline characteristics of the Vitamin D and Type 2 Diabetes (D2d) Study: a contemporary prediabetes cohort that will inform diabetes prevention efforts.  Diabetes Care. 2018;41(8):1590-1599. doi:10.2337/dc18-0240PubMedGoogle ScholarCrossref
60.
ClinicalTrials.gov. Vitamin D3 Omega3 Home Exercise Healthy Ageing and Longevity Trial (DO-HEALTH). https://clinicaltrials.gov/ct2/show/NCT01745263. Accessed April 1, 2019.
61.
Lappe  J, Watson  P, Travers-Gustafson  D,  et al.  Effect of vitamin D and calcium supplementation on cancer incidence in older women: a randomized clinical trial.  JAMA. 2017;317(12):1234-1243. doi:10.1001/jama.2017.2115PubMedGoogle ScholarCrossref
62.
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
63.
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
64.
Heaney  RP, Davies  KM, Chen  TC, Holick  MF, Barger-Lux  MJ.  Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol.  Am J Clin Nutr. 2003;77(1):204-210. doi:10.1093/ajcn/77.1.204PubMedGoogle ScholarCrossref
65.
Jones  KS, Assar  S, Harnpanich  D,  et al.  25(OH)D2 half-life is shorter than 25(OH)D3 half-life and is influenced by DBP concentration and genotype.  J Clin Endocrinol Metab. 2014;99(9):3373-3381. doi:10.1210/jc.2014-1714PubMedGoogle ScholarCrossref
66.
Flicker  L, MacInnis  RJ, Stein  MS,  et al.  Should older people in residential care receive vitamin D to prevent falls? results of a randomized trial.  J Am Geriatr Soc. 2005;53(11):1881-1888. doi:10.1111/j.1532-5415.2005.00468.xPubMedGoogle ScholarCrossref
67.
Zheng  YT, Cui  QQ, Hong  YM, Yao  WG.  A meta-analysis of high dose, intermittent vitamin D supplementation among older adults.  PLoS One. 2015;10(1):e0115850. doi:10.1371/journal.pone.0115850PubMedGoogle Scholar
68.
Bolland  MJ, Grey  A, Reid  IR.  Calcium supplements and cardiovascular risk: 5 years on.  Ther Adv Drug Saf. 2013;4(5):199-210. doi:10.1177/2042098613499790PubMedGoogle ScholarCrossref
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    1 Comment for this article
    EXPAND ALL
    Does Vitamin D alone Decrease or Increase the Risk of Fractures?
    Fatih Tufan, Assoc. Prof. | Private practice in geriatrics
    Previous studies generally reported that around 800 IU/day of vitamin D is effective in fracture prevention and 400 IU/day may not be sufficient for this indication. Nonetheless, higher doses of vitamin D are associated with increased risk of falls and fractures, especially if vitamin D levels rise above 44.7 ng/ml (1). Although the subtotal daily vitamin D treatment doses are similar between vitamin D alone and calcium plus vitamin D studies in this meta-analysis, unlike calcium plus vitamin D studies which were mostly homogenous with respect to vitamin D doses, vitamin D alone studies consisted mostly of both low dose and intermittent high dose groups.
    Secondly, secondary hyperparathyroidism (SP) occurs in only 10% to 33% of individuals with vitamin D insufficiency and vitamin D supplementation may not be beneficial in subjects without SP (2). However, baseline or follow-up intact parathyroid hormone levels are not generally reported in many studies. As a matter of fact, the presence or absence of SP was not assessed in this meta-analysis.
    In conclusion, considering these issues is important for interpretation of the results of this meta-analysis. Certain doses of vitamin D alone may be effective in the prevention of falls especially in older people with vitamin D deficiency associated with SP. On the other hand, higher doses of vitamin D may be detrimental for some older subjects.
    1. Bischoff-Ferrari HA, Dawson-Hughes B, Orav EJ, et al. Monthly high-dose vitamin D treatment for the prevention of functional decline: a randomized clinical trial. JAMA Intern Med 2016;176:175–83.
    2. 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):1612-21.
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Original Investigation
    Public Health
    December 20, 2019

    Vitamin D and Calcium for the Prevention of Fracture: A Systematic Review and Meta-analysis

    Author Affiliations
    • 1Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
    • 2Chinese Academy of Sciences Key Laboratory of Nutrition, Metabolism, and Food Safety, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences and University of the Chinese Academy of Sciences, Shanghai, China
    • 3Shanghai Institute for Biological Sciences, Chinese Academy of Sciences and University of the Chinese Academy of Sciences, Shanghai, China
    • 4Medical Research Council Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
    JAMA Netw Open. 2019;2(12):e1917789. doi:10.1001/jamanetworkopen.2019.17789
    Key Points español 中文 (chinese)

    Question  What is the available evidence for the efficacy of vitamin D with or without calcium supplementation for reducing the risk of fracture?

    Findings  This systematic review and meta-analysis of randomized clinical trials of vitamin D alone (11 randomized clinical trials with 34 243 participants) showed no significant association with risk of any fracture or of hip fracture. In contrast, daily supplementation with both vitamin D and calcium (6 randomized clinical trials with 49 282 participants) was associated with a 16% reduced risk of hip fracture.

    Meaning  In this study, neither intermittent nor daily dosing with standard doses of vitamin D alone was associated with reduced risk of fracture, but daily treatment with both vitamin D and calcium was a more promising strategy.

    Abstract

    Importance  Vitamin D and calcium supplements are recommended for the prevention of fracture, but previous randomized clinical trials (RCTs) have reported conflicting results, with uncertainty about optimal doses and regimens for supplementation and their overall effectiveness.

    Objective  To assess the risks of fracture associated with differences in concentrations of 25-hydroxyvitamin D (25[OH]D) in observational studies and the risks of fracture associated with supplementation with vitamin D alone or in combination with calcium in RCTs.

    Data Sources  PubMed, EMBASE, Cochrane Library, and other RCT databases were searched from database inception until December 31, 2018. Searches were performed between July 2018 and December 2018.

    Study Selection  Observational studies involving at least 200 fracture cases and RCTs enrolling at least 500 participants and reporting at least 10 incident fractures were included. Randomized clinical trials compared vitamin D or vitamin D and calcium with control.

    Data Extraction and Synthesis  Two researchers independently extracted data according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and assessed possible bias. Rate ratios (RRs) were estimated using fixed-effects meta-analysis. Data extraction and synthesis took place between July 2018 and June 2019.

    Main Outcomes and Measures  Any fracture and hip fracture.

    Results  In a meta-analysis of 11 observational studies (39 141 participants, 6278 fractures, 2367 hip fractures), each increase of 10.0 ng/mL (ie, 25 nmol/L) in 25 (OH)D concentration was associated with an adjusted RR for any fracture of 0.93 (95% CI, 0.89-0.96) and an adjusted RR for hip fracture of 0.80 (95% CI, 0.75-0.86). A meta-analysis of 11 RCTs (34 243 participants, 2843 fractures, 740 hip fractures) of vitamin D supplementation alone (daily or intermittent dose of 400-30 000 IU, yielding a median difference in 25[OH]D concentration of 8.4 ng/mL) did not find a reduced risk of any fracture (RR, 1.06; 95% CI, 0.98-1.14) or hip fracture (RR, 1.14; 95% CI, 0.98-1.32), but these trials were constrained by infrequent intermittent dosing, low daily doses of vitamin D, or an inadequate number of participants. In contrast, a meta-analysis of 6 RCTs (49 282 participants, 5449 fractures, 730 hip fractures) of combined supplementation with vitamin D (daily doses of 400-800 IU, yielding a median difference in 25[OH]D concentration of 9.2 ng/mL) and calcium (daily doses of 1000-1200 mg) found a 6% reduced risk of any fracture (RR, 0.94; 95% CI, 0.89-0.99) and a 16% reduced risk of hip fracture (RR, 0.84; 95% CI, 0.72-0.97).

    Conclusions and Relevance  In this systematic review and meta-analysis, neither intermittent nor daily dosing with standard doses of vitamin D alone was associated with reduced risk of fracture, but daily supplementation with both vitamin D and calcium was a more promising strategy.

    ×