By Narelle Magloire, MD, and Nancy J. Selfridge, MD
Dr. Magloire is a Clinical Teaching Fellow in the Clinical Foundations Department at Ross University School of Medicine, Commonwealth of Dominica, West Indies. Dr. Selfridge is Professor and Chair, Clinical Foundations Department, Ross University School of Medicine, Commonwealth of Dominica, West Indies.
Dr. Magloire and Dr. Selfridge report no financial relationships relevant to this field of study.
- Based on the observation that elevated homocysteine levels are associated with an increased risk of hip fractures, researchers investigated whether B vitamins, which are known homocysteine-lowering agents, might be associated with reduced risk of hip fracture.
- Vitamin B6 supplementation above the level of daily recommended doses is associated with an increased risk for hip fractures.
- The combination of folic acid and vitamin B12 supplementation did not show an overall reduction in hip fracture risk in the study participants, either during the study or in the extended follow-up.
- A secondary analysis demonstrated a decreased hip fracture incidence noted in women taking B12 with folate, compared to placebo; women represented only 23% of study participants.
SYNOPSIS: Researchers conducted a secondary analysis and extended follow-up of two large, randomized, controlled trials to show the relationship between supplementing with B vitamins and the incidence of hip fractures.
SOURCE: Garcia Lopez M, Bønaa KH, Ebbing M, et al. B vitamins and hip fracture: Secondary analyses and extended follow-up of two large randomized controlled trials. J Bone Miner Res 2017;32:1981-1989.
Hip fractures are associated with significant healthcare costs, as well as morbidity, suffering, and mortality for patients. In an elderly frail patient, a hip fracture may precipitate a cascade of circumstances, including immobilization and hospitalization, that introduce potential for life-threatening events at worst and loss of independence and autonomy at best. Studies have demonstrated an association between elevated blood homocysteine levels and incidence of hip fracture and osteoporosis. Thus, it has been hypothesized that homocysteine-lowering agents might be beneficial in reducing hip fracture incidence.1
B vitamins, particularly B12, B6 and folate, reduce homocysteine levels through their coenzyme functions in the methionine cycle, converting homocysteine to methionine, which then becomes incorporated into DNA and RNA, leading to building of proteins and lipids. Interventional trials using a randomized, controlled design to study the relationship between B vitamins and hip fractures are difficult to implement because such an infrequent primary outcome requires a large number of study participants to attain statistical significance. Accordingly, interventional studies to date have been limited in number, hampered by confounding variables (such as dietary composition), and have been unable to show a benefit solely attributable to B supplementation; however, observational studies have shown a small inverse association between vitamin B intake and hip fractures.1,2,3,4 To achieve the necessary sample size, Garcia Lopez et al performed a secondary analysis and extended follow-up of two large, randomized clinical trials previously conducted to study B vitamins as an intervention to reduce cardiovascular disease, determining if there was any effect between use of B vitamins and the risk of hip fracture.
The investigators analyzed pooled data from the Norwegian Vitamin Trial (NORVIT, December 1998 to March 2004) and the Western Norway B Vitamin Intervention Trial (WENBIT, January 2000 to October 2005), two randomized, placebo-controlled, double-blind clinical trials that included 6,837 participants. These trials were identical in design and originally looked at folic acid, vitamin B12, and vitamin B6 supplementation to reduce cardiovascular morbidity and mortality in patients with ischemic heart disease. Using a 2 × 2 factorial design, participants in these two studies were placed randomly in one of four groups to receive: 1) folic acid 0.8 mg, vitamin B12 0.4 mg, and vitamin B6 40 mg; 2) folic acid 0.8 mg and vitamin B12 0.4 mg; 3) vitamin B6 40 mg; and 4) placebo. In each group, men represented about 77% of study participants and women represented about 23%. Table 1 shows study doses compared to recommended daily allowances for these vitamins.
Table 1: B Vitamin Intervention Doses Compared to Recommended Dietary Allowances (RDA)
|
Vitamin
|
Daily Study Dose
|
RDA
|
|
Folate
|
0.8 mg
|
0.4 mg/d
|
|
B12
|
0.4 mg
|
0.0024 mg/d
|
|
B6
|
40 mg
|
1.3 mg/d
|
Collection and analysis of blood samples for B vitamin and homocysteine levels occurred at baseline, at one to two months, and at the end of the intervention. Covariates considered in the analyses included age, sex, body mass index, smoking status, hypertension, diabetes, and the presence of the 5,10-methlylenetetrahydrofolate reductase gene polymorphism associated with increased homocysteine levels.
The authors linked the combined dataset from NORVIT and WENBIT to the Norwegian hip fracture database. They used diagnostic and surgical procedure codes to identify incident hip fractures, and in cases that were not clear, they employed a comprehensive decision-making algorithm. The primary outcome was defined as a new or first hip fracture sustained by a trial participant within the study period, extended to include a post-trial follow-up observation period through December 2012. Mean plasma homocysteine levels were similar in all groups at baseline prior to intervention and were not significantly elevated, around 12 ± 5 µmol/L.
No statistically significant difference in hip fracture incidence was noted in the vitamin B12 + folate group compared to placebo. The two groups receiving any B6 supplementation demonstrated a statistically significant increase in hip fractures at 42% compared to placebo during the post-trial follow-up (P = 0.008; 95% confidence interval [CI], 9-83%), a difference not apparent during the trial period analysis. Individuals experiencing fractures had mean plasma homocysteine levels of 13.6 ± 5.2 µmol/L compared to 12.2 ± 5.0 µmol/L in those with no fractures (P < 0.01). Overall, fracture events were rare. Total fractures numbered only 43 during the trial and 236 during the post-trial follow-up out of the total 6,837 participants. When a secondary analysis was performed, a statistically significant decrease in fracture incidence was noted in women receiving B12 and folate compared to placebo (hazard ratio, 1.87; 95% CI, 1.14-3.07), a relationship not noted in men within this group.
COMMENTARY
The prevention of hip fractures is a high priority because of the effect on patients, families, communities, and economies.5 Although homocysteine appears to be a marker for increased risk of hip fracture, homocysteine-lowering therapy, in particular B vitamin supplementation, has not demonstrated success in reducing fracture risk in clinical trials.2,3,4 This analysis of two large Norwegian trials examining B vitamin supplementation, although adequately powered, also failed to show a preventive benefit for the population studied.
In addition to the size of the study population and the addition of the extended follow-up, study strengths include the blood analysis results that analyzed baseline mean homocysteine levels and the effects of supplementation, showing that B12 and folate supplementation (with or without B6) had a statistically significant effect on lowering homocysteine levels, whereas placebo and B6 did not. In fact, any B6 supplementation appeared to increase fracture risk, an effect not mitigated by the addition of B12 and folate. Secondary stratified analyses for multiple factors known to affect risk of osteoporosis and hip fractures were another strength. Only female gender emerged as a covariate having an effect on outcomes, and this was only for women taking folate and B12.
A study weakness is that data were pooled from participants who all had underlying ischemic heart disease in the original studies, and who were relatively young (51-73 years of age) considering the primary outcome of hip fracture. Further,
only 23% of participants were women; thus, the majority of study participants were not representative of the aging population at greatest risk. The results may not be generalizable to a more diverse or representative population. Dietary data were not collected in this study. Although plasma B vitamin levels were monitored at baseline and during intervention, other dietary factors, such as calcium, magnesium, vitamin D, and protein intake, influence fracture risk.
When patients seek advice about vitamin supplementation, providers can share that supplementation with B12 and folate appears to lower homocysteine levels, but no benefit is apparent in reducing hip fracture risk except in women. Supplementation with B6 at levels significantly greater than the recommended daily allowance should be discouraged because of the clear association with increased hip fracture risk. In the meantime, we await additional bench research to clarify complex biochemical and physiologic relationships, including the role of homocysteine, in the development of osteoporosis and related fracture risk.
REFERENCES
- Gjesdal CG, Vollset SE, Ueland PM, et al. Plasma homocysteine, folate and vitamin B12 and the risk of hip fracture; the Hordaland homocysteine study. J Bone Miner Res 2007;22:747-756.
- Koh ZD, Wang R, Ang LW, etal. Dietary B vitamin intake and risk of hip fracture: The Singapore Chinese Health study. Osteoporos Int 2013;7:2049-2059.
- Van Wijngaarden JP, Swart KM, Enneman AW, et al. Effect of daily vitamin B-12 and folic acid supplementation on fracture incidence in elderly individuals with an elevated plasma homocysteine concentration: B-PROOF, a randomized controlled trial. Am J Clin Nutr 2014;100:1578-1586.
- Gommens J, Yi Q, Eikelboom JW, et al. The effect of homocysteine lowering with B-vitamins on osteoporotic fractures in patients with cerebrovascular disease: Substudy of VITATOPS, a randomized placebo-controlled trial. BMC Geriatr 2013;13:88.
- Gjertsen JE, Baste V, Fevang JM, et al. Quality of life following hip fractures; Results from the Norwegian hip fracture register. BMC Musculoskelet Disord 2016;17:265.
