B6 & B12 Hip Fracture in Postmenopausal Women

Alzheimer's, cardiovascular, and other chronic diseases; biomarkers, lifestyle, supplements, drugs, and health care.
Post Reply
Plumster
Senior Contributor
Senior Contributor
Posts: 620
Joined: Mon Oct 30, 2017 6:19 pm

B6 & B12 Hip Fracture in Postmenopausal Women

Post by Plumster »

I may need to cut back on these two Bs . . . Study linked below.
May 10, 2019
JAMA Network Open
"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"

Question: Are high intakes of vitamins B6 and B12 associated with an increased risk of hip fracture?

Findings: In a cohort study of 75 864 US postmenopausal women, 2304 had a hip fracture. A combined high intake of vitamins B6 and B12 was associated with an increased risk of hip fracture.

Meaning: These results add to the evidence suggesting that caution should be used in vitamin supplementation when there is no apparent deficiency.
https://jamanetwork.com/journals/jamane ... le/2733176
e3/4 MTHFR C677T/A1298C COMT V158M++ COMT H62H++ MTRR A66G ++ HLA DR
BrianR
Senior Contributor
Senior Contributor
Posts: 298
Joined: Tue Oct 02, 2018 12:32 pm
Location: Central Florida

Re: B6 & B12 Hip Fracture in Postmenopausal Women

Post by BrianR »

It does seem somewhat concerning, although it's only an associational study. It would have been great if they could have sampled populations for bone density or other specific physiological changes, or even learning why those taking more B6/12 were doing so - were there other potential contributors to the outcomes?

Of course, it would also be great if B vitamin supplements wouldn't tend to provide dosing at such high levels.

Some analysis from the paper:
Possible Mechanisms
A possible biological explanation for the findings in the present study is not clear. The magnitude of intakes of vitamins B6 andB12 associated with an increased risk of hip fracture in our study far exceeded the recommended dietary allowances (RDAs) (1.3-1.7 mg/d for vitamin B6 and 2.4 μg/d for vitamin B12).

Possible adverse effects of high-dose vitamin B6 supplementation have previously been suggested. High doses (≥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. Preliminary work suggested that high vitamin B6 concentrations might accelerate bone loss by counteracting the modulating influence of estrogens on steroid receptors. A recent paradox theory proposes that large doses of pyridoxine, the inactive form of vitamin B6 included in supplements and found in foods, inhibits the active form pyridoxal phosphate.

We do not have an explanation for the mechanism by which vitamin B12 may contribute to increased fracture risk. However, as summarized in Table 4 and in eTable 5 in the Supplement, 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 RCTs giving vitamin B12 and/or folic acid alone (without vitamin B6).

A possible explanation for the interaction between total vitamin B6 intake and BMI is not clear. At low BMI, fracture risk was higher, and a larger number of incident hip fractures thus occurred, yielding higher statistical power. We speculate that the possible mechanism of excessive vitamin B6 exposure increasing fall risk through neurological symptoms could particularly aggravate fracture risk in women with low BMI, who are more prone to fracturing their hip when experiencing a fall. However, adjustment for falls had little influence on the estimates, and the association between falls and fracture risk was not altered by adjustment for vitamins B6 and B12 intakes. It also could be that the possible interaction between vitamin B6 and the steroid receptor might be most influential in lean women, who have a reduced capacity for production of adipose-derived estrogens.

Strengths and Limitations
Our study has strengths and limitations. We were able to follow up a large cohort of women with repeated detailed assessments of diet, supplement use, and other possible confounding factors. However, we cannot exclude the possibility that individuals started taking supplements due to ill health. In addition, all information on vitamin intake and confounders was collected by questionnaires, with their inherent limitations. Although residual confounding could be present, our results were not substantially influenced by adjustment for indicators of frailty or disease or a long list of other possible confounders. Another limitation was the self-report of hip fractures. However, in sensitivity analyses censoring participants at age 80 years (thus omitting the oldest, in whom underreporting of fracture could be an issue), the association for total vitamin B6 intake was marginally stronger. An additional limitation is that the findings may be applicable only to women of white race/ethnicity.

The results for supplemental vitamin B6 are puzzling because all categories above the reference category have similar increases in risk. Also, intakes of different supplements are correlated, making it challenging to disentangle specific associations. Nevertheless, our results were adjusted for intake of calcium, vitamin D, and retinol, and the differences between the model adjusted for age and questionnaire cycle and the fully adjusted models were modest.

We did not control for multiple hypothesis testing. However, our analyses were based on the RCT results, in which the highest fracture risk was found in those treated with high doses of both vitamins. A low proportion of the women were in the low-intake category of both vitamins. Yet, compared with the group with a medium intake of both vitamin B6 (2 to <35 mg/d) and vitamin B12 (10 to <20 μg/d), the risk was still significantly increased in those with a high intake of both vitamins (RR, 1.25; 95% CI, 1.03-1.51).

Implications
The RDAs are established to meet the nutritional requirements of almost the entire population. Despite that, use of high-dose vitamin supplementation far exceeding the RDAs is common, often without any definite indication and in the absence of clear evidence of benefit.

Our results are in line with several reports suggesting that unexpected adverse effects can occur with high-dose vitamin supplementation. For example, high-dose beta-carotene supplementation increased the risk of lung cancer in smokers, and high-dose vitamin E supplementation may increase all-cause mortality. Higher risk of fracture was reported in 2 RCTs after treatment with annual megadoses of vitamin D, and possible adverse effects of homocysteine-lowering treatment with B vitamins have been observed, including a potentially increased risk of cancer. Although we acknowledge the limitations of our cohort design, the findings herein add to the body of literature that suggests caution should be used in vitamin supplementation when there is no apparent deficiency.
Post Reply