High doses of vitamin B supplementation may put women at risk for fracture, according to a new study.
In an analysis of over 75,000 postmenopausal women, higher total intakes of vitamin B6 and vitamin B12 were both associated with a higher relative risk of hip fracture, Haakon E. Meyer, MD, PhD, of the University of Oslo in Norway, and colleagues reported in JAMA Network Open:
- Vitamin B6: RR 1.29 (95% CI 1.04-1.59 for an intake of ≥35 vs <2 mg/d; P=0.06 for linear trend)
- Vitamin B12: RR 1.25 (95%CI 0.98-1.58 for an intake of ≥30 vs <5 μg/d; P=0.02 for linear trend)
This relative risk was still significantly elevated when intake of the vitamins was isolated to supplements only — i.e., not including diet:
- Vitamin B6: RR 1.41 (95% CI 1.10-1.80 for an intake of ≥25 vs 0 mg/d)
- Vitamin B12: RR 1.26 (95% CI 1.01-1.56 for an intake of ≥25 vs 0 μg/d)
Postmenopausal women who reported high intakes of both vitamins — 35 mg/d of B6 and 20 μg/d of B12 — saw the highest associated risk for hip fracture compared with women who averaged the lowest intake — <2 mg/d of B6 and <10 μg/d of B12. Specifically, women who fell into the highest intake group for both vitamins had a nearly 50% higher risk for fracture compared with women who had low intakes of vitamin B6 and B12 (RR 1.47, 95% CI 1.15-1.89).
“High intakes were due to use of supplements,” noted the researchers, adding that the “findings add to previous studies suggesting that vitamin supplements should be used cautiously because adverse effects can occur.”
Women who averaged medium B6 and high B12 intake saw the second highest elevated risk for hip fracture versus those in a low-low intake for B6 and B12 (RR 1.31, 95% CI 1.07-1.60).
The analysis included women who participated in the Nurses’ Health Study, who were followed from June 1984 to May 2014. Among the 75,864 postmenopausal women included, 2,304 had a hip fracture during follow-up, with an average age of hip fracture of approximately 76. These women who experienced a hip fracture also had an average body-mass index of 24.3.
Median intakes of B6 and B12 were 3.6 mg/d and 12.1 μg/d, respectively, far exceeding the recommended dietary allowances of 1.3-1.7 mg/d for vitamin B6 and 2.4 μg/d for vitamin B12.
Information on diet and supplement intake were collected through semi-quantitative food frequency questionnaires collected every 4 years. Data on hip fractures and other clinical factors — some of which included smoking status; exercise frequency; menopausal status; menopausal hormone therapy use; osteoporosis, cardiovascular disease, diabetes, and cancer history; and use of corticosteroids and furosemide-like and/or thiazide diuretics — were collected through biennial questionnaires.
Regarding possible mechanisms of action for the relationship, the researchers speculated that high doses of the vitamins (500 mg/d) might increase the risk of falling because neurological symptoms, including ataxia, neuropathy, and decreased muscle tone have been reported, and milder neurological symptoms have been observed at doses of approximately 100 mg/d as adverse effects.
In addition, “preliminary work suggested that high vitamin B6 concentrations might accelerate bone loss by counteracting the modulating influence of estrogens on steroid receptors,” Meyer and co-authors added.
“We do not have an explanation for the mechanism by which vitamin B12 may contribute to increased fracture risk,” they wrote. “However … a high intake of vitamin B12 and a low intake of vitamin B6 were not associated with increased risk, which is in agreement with a meta-analysis of [randomized controlled trials] giving vitamin B12 and/or folic acid alone (without vitamin B6).”
Meyer’s group noted that although the cohort design and use of food frequency questionnaires were limitations of the study, the findings still “add to the body of literature that suggests caution should be used in vitamin supplementation when there is no apparent deficiency.”
The study was supported by grants from the National Institutes of Health.
Meyer and co-authors reported having no conflicts of interest.