Association of High Intakes of Vitamins B6 and B12 From Food and Supplements With Risk of Hip Fracture Among Postmenopausal Women in the Nurses' Health Study

JAMA Netw Open. 2019 May 3;2(5):e193591. doi: 10.1001/jamanetworkopen.2019.3591.


Importance: Vitamin supplementation far exceeding recommended doses is popular in segments of the population. However, adverse effects can occur. In a previous secondary analysis of combined data from 2 double-blind randomized clinical trials (RCTs), an unexpected increased risk of hip fracture was found among those treated with high doses of vitamin B6 in combination with vitamin B12.

Objectives: To study if high intakes of vitamins B6 and B12 from food and supplements were associated with a risk of hip fracture in the Nurses' Health Study and to investigate whether combined high intakes of both vitamins conferred a particularly increased fracture risk.

Design, setting, and participants: In this prospective cohort study, 75 864 postmenopausal women in the United States were followed up from June 1984 through May 2014. The dates of analysis were July 2016 to June 2018. Information on hip fracture and a wide range of potential confounders was collected at baseline and with biennial follow-up questionnaires. Extensive dietary information was collected approximately every 4 years with a semiquantitative food frequency questionnaire. Relative risks (RRs) were calculated by Cox proportional hazards regression, with cumulative average intakes of vitamins B6 and B12 as main exposures, adjusting for potential confounders.

Main outcome and measure: Hip fracture.

Results: During follow-up, 2304 of 75 864 women had a hip fracture. Among the women with hip fractures, the median (range) age at hip fracture was 75.8 (46.7-93.0) years and the mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) was 24.3 (4.6). Median (interquartile range) cumulative average intakes of total vitamins B6 and B12 were 3.6 (4.8) mg/d and 12.1 (11.7) μg/d, respectively. Both vitamin B6 (RR, 1.29; 95% CI, 1.04-1.59 for an intake of ≥35 vs <2 mg/d; P = .06 for linear trend) and vitamin B12 (RR, 1.25; 95% CI, 0.98-1.58 for an intake of ≥30 vs <5 μg/d; P = .02 for linear trend) were associated with increased fracture risk. Risk was highest in women with a combined high intake of both vitamins (B6 ≥35 mg/d and B12 ≥20 μg/d), exhibiting an almost 50% increased risk of hip fracture (RR, 1.47; 95% CI, 1.15-1.89) compared with women with a low intake of both vitamins (B6 <2 mg/d and B12 <10 μg/d).

Conclusions and relevance: In this cohort study, a combined high intake of vitamins B6 and B12 was associated with an increased risk of hip fracture. The intakes were far higher than the recommended dietary allowances. These findings add to previous studies suggesting that vitamin supplements should be used cautiously because adverse effects can occur.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Aged, 80 and over
  • Cohort Studies
  • Dietary Supplements / adverse effects*
  • Double-Blind Method
  • Female
  • Hip Fractures / chemically induced*
  • Hip Fractures / epidemiology
  • Humans
  • Middle Aged
  • Postmenopause
  • Prospective Studies
  • Risk Factors
  • United States / epidemiology
  • Vitamin B 12 / adverse effects*
  • Vitamin B 6 / adverse effects*


  • Vitamin B 6
  • Vitamin B 12