B Vitamins and Bone Fracture Risk

Reference

Meyer HE, Willett WC, Fung TT, Holvik K, Feskanich D. 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;2(5):e193591.

Study Objective

To determine 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 (NHS) and to investigate whether combined high intakes of both vitamins conferred a particularly increased fracture risk.

Design

The NHS is a prospective cohort study evaluating data from biennial questionnaires issued from June 1984 through May 2014.

Participants

Participants included 75,864 postmenopausal women in the United States.

Participants were all registered nurses who enrolled in the NHS.

Study Parameters Assessed

On every biennial follow-up questionnaire, researchers requested information about hip fracture, including the date of occurrence and a description of the circumstances. They also identified hip fractures from death records. Hip fractures caused by cancer or “major traumatic events” were excluded.

The researchers assessed diet with a semiquantitative food frequency questionnaire (FFQ) in 1984, 1986, and every 4 years thereafter until 2010. Participants reported their habitual frequency of consumption over the previous year for specified serving sizes of more than 130 foods. Daily energy and nutrient intakes were calculated from the total diet.

The FFQ requested information on current use of supplements, such as vitamin B₆, folic acid, vitamin B complex, vitamin B₁₂–only supplements (beginning in 1998), multivitamins, vitamin A, vitamin D, and calcium

All biennial follow-up questionnaires assessed the following measures: weight; hours per week spent in recreational activities; smoking status; menopausal status and use of postmenopausal hormone therapy; diagnoses of cancer, diabetes, cardiovascular disease, and osteoporosis; and use of thiazide diuretics, furosemide-like diuretics, and oral corticosteroids.

Beginning in 1992, questionnaires included questions concerning difficulties with balance, climbing a flight of stairs, or walking 1 block, and from 1998 onward, they included questions on falls and pernicious anemia. In 1992, 1996, and 2000, questionnaires requested self-rated general health status.

Primary Outcome Measures

Incident hip fractures

Vitamin B₆, vitamin B₁₂, and “other nutrient intakes that were cumulatively averaged over follow-up.”

Key Findings

Researchers analyzed data from July 2016 to June 2018. Median follow-up time was 20.9 years.

There were 2,304 fracture cases out of the 74,864 women cohort (3.04%). The median age at the time of hip fracture was 75.8 years (age range: 46.7-93.0 years).

These women had a total vitamin B₆ intake and vitamin B₁₂ intake of 3.6 (4.8) mg/d and 12.1 (11.7) μg/d, respectively.

Physical activity increased and smoking prevalence decreased with higher intakes of both vitamins. Intakes of other micronutrients were also higher in those with increased intakes of vitamins B₆ and B₁₂, whereas caffeine and alcohol consumption was lower.

Compared with the reference category of total vitamin B₆ less than 2 mg/d, an intake of at least 35 mg/d was associated with a non-statistically significant increase in risk of hip fracture after adjusting for all covariates (relative risk [RR], 1.29; 95% confidence interval [CI], 1.04-1.59; P=.06 for linear trend).

For vitamin B₆ from supplements only, those consuming no vitamin B₆ supplements had the lowest risk compared with a similar increased risk in the other groups.

Their conclusion contradicts several earlier studies that looked at the potential impact of B vitamins on fracture risk and found no significant interactions.

For total vitamin B₁₂, intakes of at least 30 μg/d were associated with a nonsignificant increased risk of hip fracture compared with intakes of less than 5 μg/d (RR, 1.25; 95% CI, 0.98-1.58), and risk increased linearly with increasing intake (RR, 1.01; 95% CI, 1.00-1.03 per 10-μg/d increase in total intake; P=.02 for linear trend).

The interaction term for the 2 vitamins on fracture risk was not significant.

In fully adjusted models that included adjustment for intake from supplements, there was no clear association between vitamin B₆ from diet only and hip fracture (RR, 1.03; 95% CI, 0.91-1.16 per 1-mg/d increase in intake from food only; P=.67 for linear trend) or between vitamin B₁₂ from diet only and hip fracture (RR, 1.01; 95% CI, 0.99-1.02 per 1-μg/d increase in intake from food only; P=.54 for linear trend).

Women with a high intake of both vitamins had a significantly increased risk of hip fracture compared with the reference category of a low intake of both vitamins (RR, 1.47; 95% CI, 1.15-1.89). Among women in the medium-intake categories for both vitamins, risk was not significantly elevated (RR, 1.18; 95% CI, 0.98-1.42). Few women had low intakes of 1 vitamin and high intakes of the other.

Practice Implications

This study raises intriguing questions about the practice and safety of nutritional supplementation. The authors state, “The risk was highest in women with a combined high intake of both vitamins, exhibiting an almost 50% increased risk of hip fracture compared with women with a low intake of both vitamins. High intakes were due to use of supplements.”

However, their data set has many limitations. First, this was an observational study, and all information on dietary supplement use was gathered using questionnaires, a method that has inherent fallibilities. Second, as the authors state, “intakes of different supplements are correlated, making it challenging to disentangle specific associations.” Third, they could not determine or correct for the possibility that participants started taking dietary supplements due to ill health, which would not be surprising.

Their conclusion contradicts several earlier studies that looked at the potential impact of B vitamins on fracture risk and found no significant interactions.

A 2018 meta-analysis of clinical trials published in the Journal of Bone and Mineral Research and involving 1,021 volunteers did not find a significant association of folic acid and vitamin B₁₂ dietary supplements and fracture incidence.¹

A 2017 randomized, controlled clinical trial involving 4,810 women and published in the Journal of Bone and Mineral Research similarly found no significant effect of B-vitamin supplementation (folic acid 2.5 mg/d, vitamin B₆ 50 mg/d, and vitamin B₁₂ 1 mg/d, form of vitamins not specified) on fracture risk.² Also, the risk of any non-spinal fracture in this study was similar among those randomized to vitamin or placebo (hazard ratio [HR]=1.08; 95% CI, 0.88, 1.34), as were risks of hip (HR=0.99; 95% CI, 0.43, 2.29), wrist (HR=1.30; 95% CI, 0.80, 2.11), and other fracture (HR=1.03; 95% CI, 0.82, 1.30). They concluded that B vitamins neither reduced nor increased risk for non-spinal or spinal fractures, stating, “Overall, our results add to the growing body of evidence from randomized trials, demonstrating minimal effect of B vitamin supplementation on risk of fracture.”

In 2014, another double-blind, randomized, placebo-controlled clinical trial published in the American Journal of Clinical Nutrition evaluated whether folic acid and vitamin B₁₂ supplementation can reduce fracture risk in patients with elevated homocysteine.³ Women aged 65 years and more (N=2,919) who had elevated homocysteine were enrolled in the study. Homocysteine significantly declined in the treatment arm, but there were no differences in fractures.

There are no recent primary studies that evaluated only vitamins B₁₂ and B₆ for fracture risk, and the closest comparison is a secondary analysis of a 1984 4-arm clinical trial in Norway.⁴

The Norwegian study was originally designed to evaluate the impact of

1. folic acid (0.8 mg/d) plus vitamin B₁₂ (as cyanocobalamin, 0.4 mg/d) plus vitamin B₆ (as pyridoxine hydrochloride, 40 mg/d),
2. folic acid plus B₁₂,
3. B₆ alone, or
4. placebo on morbidity and mortality in patients with preexisting ischemic heart disease.

In the secondary analysis, the researchers evaluated 2 time periods: For the first time period, during the study, they used the data generated during the interventions, and then they compared that with participant health records for an extended period of time (approximately 7 additional years) after the clinical trial ended. During the intervention, there were no clinically significant increases in fracture risk. However, during extended follow-up (median 11.2 years from trial start), those taking vitamin B₆ alone had a 42% higher risk of hip fracture (HR 1.42; 95% CI, 1.09-1.83) compared to those not taking B₆.

Taken together, studies on vitamins B₆ and B₁₂ intake and fracture risk are conflicting. The observational study under review is considered a lesser level of evidence when compared to interventional studies done in the past. While this study implies there may be an increased fracture risk, there is little substantiation of this observation from interventional trials.