Vitamin D and Calcium for the Prevention of Fracture: A Systematic Review and Meta-analysis | Complementary and Alternative Medicine | JAMA Network Open | JAMA Network
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    1 Comment for this article
    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.
    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.


    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.