B vitamins and risk of bone fractures

Relation

Meyer HE, Willett WC, Fung TT, Holvik K, Feskanich D. Association of High Intakes of Vitamin B₆and B₁₂of foods and supplements associated with hip fracture risk in postmenopausal women in the Nurses' Health Study.JAMA network opened. 2019;2(5):e193591.

Study objective

To determine whether high intake of vitamin B₆and B₁₂from foods and dietary supplements were associated with a risk of hip fractures in the Nurses' Health Study (NHS) and to investigate whether a combined high intake of both vitamins resulted in a particularly increased risk of fractures.

Draft

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

Participant

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

Participants were all registered nurses enrolled in the NHS.

Study parameters assessed

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

Researchers assessed diet in 1984, 1986 and every 4 years thereafter until 2010 using a semi-quantitative dietary questionnaire (FFQ). Participants reported their usual frequency of consumption over the past year for specific portion sizes of more than 130 foods. Daily energy and nutrient intake was calculated from total diet.

The FFQ requested information on current use of dietary supplements such as vitamin B₆Folic acid, vitamin B complex, vitamin B₁₂–only dietary supplements (from 1998), multivitamins, vitamin A, vitamin D and calcium

All biennial follow-up questionnaires assessed the following measures: weight; hours per week spent on leisure 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.

From 1992, the questionnaires included questions about balance problems, climbing stairs or walking a block, and from 1998 questions about falls and pernicious anemia. In 1992, 1996 and 2000 questionnaires asked about self-rated general health.

Primary outcome measures

Incident hip fractures

Vitamin B₆Vitamin B₁₂and “other nutrient intakes cumulatively averaged over follow-up.”

Key insights

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

There were 2,304 fracture cases from the cohort of 74,864 women (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 total vitamin B₆Intake and vitamin B₁₂Intake of 3.6 (4.8) mg/d or 12.1 (11.7) μg/d.

Physical activity increased and smoking prevalence decreased with higher intakes of both vitamins. Intake of other micronutrients was also higher in those with increased vitamin B intake₆and B₁₂while caffeine and alcohol consumption were lower.

Compared to the reference category total vitamin B₆less than 2 mg/d, intake of at least 35 mg/d was associated with a statistically nonsignificant increase in hip fracture risk 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 B₆only from dietary supplements, those who do not consume vitamin B₆Dietary supplements had the lowest risk compared to a similarly increased risk in the other groups.

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

For total vitamin B₁₂Intakes of at least 30 μg/d were associated with a nonsignificantly increased risk of hip fracture compared with intakes of less than 5 μg/d (RR, 1.25; 95% CI, 0.98-1.58), and the 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 supplement use, there was no clear association between vitamin B₆from diet alone and hip fracture (RR, 1.03; 95% CI, 0.91-1.16 per 1 mg/day increase in intake from food alone;P= 0.67 for linear trend) or between vitamin B₁₂from diet alone and hip fracture (RR, 1.01; 95% CI, 0.99-1.02 per 1 μg/d increase in intake from food alone;P=.54 for linear trend).

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

Practice implications

This study raises intriguing questions about the practice and safety of supplementation. The authors note: "Risk was highest in women with high combined intakes of both vitamins, with a nearly 50% increased risk of hip fracture compared to women with low intakes of both vitamins. High intakes were due to supplement use."

However, your dataset has many limitations. First, this was an observational study and all information about supplement use was collected using questionnaires, a method that has inherent fallibilities. Second, as the authors noted, “the use of different supplements is correlated, making it difficult to disentangle specific associations.” Third, they could not detect or correct for the possibility that participants began taking supplements for health reasons, which would not be surprising.

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

A meta-analysis of clinical trials published in 2018Journal of Bone and Mineral Researchand including 1,021 volunteers, no significant association of folic acid and vitamin B was found₁₂Dietary supplements and fracture incidence.¹

A 2017 randomized, controlled clinical trial of 4,810 women published inJournal of Bone and Mineral ResearchThere was also no significant effect of B vitamin supplementation (folic acid 2.5 mg/d, vitamin B₆50 mg/day and vitamin B₁₂1 mg/d, vitamin form not specified) on fracture risk.²Additionally, the risk of non-spine 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 was the risk of hip (HR=0.99; 95% CI, 0.43, 2.29), wrist (HR= 1.30; 95% CI, 0.80, 2.11) and other fractures (HR = 1.03). ; 95% CI, 0.82, 1.30). They concluded that B vitamins neither reduced nor increased the risk of non-spine or spinal fractures, noting: "Overall, our results add to the growing body of evidence from randomized trials showing a minimal effect of B vitamin supplementation on fracture risk."

In 2014, another double-blind, randomized, placebo-controlled clinical trial was publishedAmerican Journal of Clinical Nutritionevaluated whether folic acid and vitamin B₁₂Nutritional supplementation may reduce the risk of fractures in patients with elevated homocysteine.³Women aged 65 years and over (N=2,919) with elevated homocysteine ​​were included in the study. Homocysteine ​​decreased significantly in the treatment arm, but there were no differences in fractures.

There are no recent primary studies that have examined only vitamin B₁₂and B₆for fracture risk, and the closest comparison is a secondary analysis of a 4-arm clinical trial from 1984 in Norway.⁴

The Norwegian study was originally designed to assess the effects of

1. Folsäure (0,8 mg/d) plus Vitamin B₁₂ (als Cyanocobalamin, 0,4 mg/Tag) plus Vitamin B₆ (als Pyridoxinhydrochlorid, 40 mg/d),
2. Folsäure plus B₁₂,
3. B₆ alleine, bzw
4. Placebo auf Morbidität und Mortalität bei Patienten mit vorbestehender ischämischer Herzkrankheit.

In the secondary analysis, the researchers evaluated 2 time periods: For the first period, during the study, they used the data generated during the interventions and then compared these with the participants' health records over a longer period of time (approximately 7 additional years) after the end of the clinical trial. There was no clinically significant increase in fracture risk during the procedure. During a longer follow-up period (median 11.2 years from the start of the experiment), those who received vitamin B₆alone had a 42% higher risk of hip fracture (HR 1.42; 95% CI, 1.09-1.83) compared to those who did not take B₆.

Taken together, studies on vitamin B₆and B₁₂Ingestion and fracture risk are contradictory. The observational study under review is considered to be less evidence-based compared to previous intervention studies. While this study implies that there may be an increased risk of fracture, there is little evidence to support this observation from interventional studies.