Vitamin B12, bone mineral density and fracture risk in adults: A systematic review

Macêdo, Luciana Leal Gomes de; Carvalho, Cecilia Maria Resende Gonçalves de; Cavalcanti, Janaína Costa; Freitas, Betania de Jesus e Silva de Almendra

doi:10.1590/1806-9282.63.09.801

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REVIEW ARTICLES • Rev. Assoc. Med. Bras. 63 (9) • Sept 2017 • https://doi.org/10.1590/1806-9282.63.09.801 linkcopy

Vitamin B12, bone mineral density and fracture risk in adults: A systematic review

Vitamina B12, densidade mineral óssea e risco de fraturas em adultos: uma revisão sistemática

Authorship SCIMAGO INSTITUTIONS RANKINGS

Summary

Objective: To consolidate information available on the effect of vitamin B12 on bone mineral density and fracture risk, with emphasis on clinical trials, observational and longitudinal data conducted in humans.

Method: A systematic review of the literature of the past decade on the role of vitamin B12 in bone mineral density and fracture risk in subjects of all ages and both sexes was performed by means of a PubMed, Science Direct, Medline and SciELO database search. Articles included in this review were identified using the search terms: B12 Vitamin and Bone Mineral Density and Vitamin B12 and Risk of Fractures. Evidence quality of the included articles was evaluated by GRADE system.

Results: A total of 25 original studies were identified. After reviewing the titles and abstracts of articles, only 17 articles met the inclusion criteria. The present review provides evidence that the role of vitamin B12 on bone mineral density or fracture risk should be further elucidated. Controversies are explained by heterogeneity of methodologies used for the diagnosis of vitamin B12 and also by differences among populations investigated on the studies.

Conclusion: A real effect of vitamin B12 deficiency in bone health and the mechanisms associated with bone metabolism is not well established yet. It is extremely important to carry out more clarifying studies about this theme, especially with vulnerable groups such as postmenopausal and elderly women, as is well-known that they are greatly affected by deficiency of this vitamin.

Keywords:
bone health vitamin; B12 vitamin supplementation; fracture risk

Authors and year	Design and participants	Variables	Intervention	Results Main	Quality of evidence (GRADE)
Epidemiological studies
Baines et al., 2007¹⁰	Cross-sectional observational study 328 postmenopausal British women	Plasma homocysteine, serum levels of vitamins B6, B9 and B12, genotype of the MTHFR enzyme, and BMD	–	Folate levels were significantly associated with BMD (p=0.02), but vitamin B6 and B12 were not (p=0.91 and p=0.82, respectively)	Moderate
Gjesdal, et al., 2007¹⁶	Prospective longitudinal observational study 4,766 elderly Norwegian men and women, aged 65-67 years, for 13 years	Plasma levels of homocysteine, vitamins B9 and B12, polymorphism of genotypes 677C ® T and 1298A ® C MTHFR, and risk of fractures	–	Vitamin B12 and the MTHFR genotype were not associated with hip fractures Homocysteine increased the risk of fracture in both genders. Only among women there was an inverse association between folate levels and fracture risk	High
Yazdanpanah et al., 2007¹⁸	Prospective longitudinal observational study 5304 Dutch men and women aged 55 or over for 6 to 7 years	Association of dietary intake of vitamins B2, B6, B9 and B12 with BMD and risk of fractures	–	There was no association of vitamins B9 and B12 with BMD and the risk of fractures Positive association of vitamins B6 and B2 with BMD (b=0.09, p=1 × 10-8 b=0.06, p=0.002, respectively) Pyridoxine intake was inversely correlated with fracture risk	Low
Cagnacci et al., 2008¹⁹	Prospective longitudinal observational study 117 postmenopausal women, aged 54 years on average, for 5 years	Association between serum levels of vitamins B9 and B12, homocysteine and BMD	–	There was no association of vitamin B12 and homocysteine with BMD The rate of BMD variation over the 5 years correlated positively with serum folate levels (p=0.011)	Low
McLean et al., 2008³	Longitudinal observational study 1002 men and women with mean age of 75 years for 4 years	Plasma concentrations of vitamins B6, B9 and B12, and homocysteine with bone loss and risk of hip fracture in elderly men and women	–	Low concentrations of vitamins B12 and B6 were associated with increased risk of hip fracture. Lower plasma concentration of vitamin B6 was associated with greater bone loss	Moderate
Rejnmark et al., 2008²⁰	Prospective longitudinal observational study 1,869 Danish women in perimenopause, aged between 43 and 58 years, for 10 years	Association of dietary intake and supplementation of vitamins B2, B9 and B12 with BMD and fracture risk		There was no positive association between B12, B9, B2 and BMD or fracture risk. At 5 years, cross-sectional analyzes indicated that folic acid intake correlated significantly with BMD	Low
Bozkurt et al., 2009²¹	Cross-sectional observational study 178 postmenopausal Turkish women	Relation of serum levels of homocysteine, vitamins B9 and B12 with BMD		Serum levels of vitamin B12, but not those of B9, were associated with osteoporosis in the lumbar spine and neck of the femur Homocysteine levels were found to be higher in women with osteoporosis compared to normal women or those with osteopenia	Moderate
Holstein et al., 2009¹⁵	Cross-sectional observational study 94 German women and men treated with hip arthroplasty	Association of serum levels of homocysteine, vitamins B6, B9 and B12 with OC (bone formation marker), TRAP (bone resorption marker), BMD and trabecular thickness	–	There was no positive association between vitamin B12, as well as the other vitamins analyzed, and BMD or homocysteine OC levels are lower in individuals with low levels of B-complex vitamins. Trabecular thickness is lower in individuals with low B9 concentrations.	Moderate
Halıloglu et al., 2010¹⁴	Cross-sectional observational study 120 postmenopausal women	Relation of serum levels of homocysteine, vitamins B9 and B12 with BMD and markers of bone remodeling (BAP and CTx)		There was no positive association of vitamins B12 and B9 with BMD and markers of bone remodeling. Homocysteine levels were higher in osteoporotic women but were not related to BMD	Moderate
Kakehasi et al., 201²¹	Cross-sectional observational study 70 postmenopausal Brazilian women (50 to 79 years)	Plasma levels of vitamin B12 and BMD	–	There was no association between plasma levels of vitamin B12 and BMD (p=0.93)	Low
Rumbak et al., 2012²²	Cross-sectional observational study 131 Croatian women aged between 45 and 65 years	Relation of serum levels of vitamin B12, plasma levels of homocysteine and red blood cells and serum levels of vitamin B9 to BMD	–	There was no association of vitamins B12 and B9 and homocysteine with BMD	Low
Dai et al., 2013¹⁷	Prospective longitudinal observational study 63154 Chinese women and men, aged between 45 and 74 years, for 13.8 years	Association of dietary intake of vitamins B1, B2, B3, B6, B9 and B12 with the risk of hip fractures		Inverse relationship between dietary intake of vitamin B6 and risk of hip fracture in older women but not in men There was no association between the dietary intake of B12 and the other B vitamins and the risk of fractures	Moderate
Bailey et al., 2015²³	Cross-sectional observational study 2806 American women aged ≥ 50 years	Association of homocysteine and vitamin B12 with BMD and risk of osteoporosis	–	High levels of homocysteine and methyl malonic acid were associated with increased risk of osteoporosis in the lumbar spine. Vitamin B12 was not directly associated with BMD	High
Clarke at al, 2015⁹	Cross-sectional observational study 110 women and men over the age of 20 under treatment for celiac disease	Association of nutritional status of vitamins B2, B6, B9 and B12 with BMD	–	Only serum levels of vitamin B12 were significantly determining for femoral and hip BMD in men but not in women	Low
Bahtiri et al., 2015¹³	Cross-sectional observational study 139 postmenopausal women	Association of serum levels of homocysteine and vitamin B12 with BMD		Serum homocysteine levels were significantly higher in osteoporotic women than in the other groups and inversely correlated with lumbar spine and femoral neck BMD. Serum vitamin B12 levels were not associated with BMD	Low
Clinical trials
Gommans et al., 2013²⁴	Randomized, double-blind, placebo-controlled clinical trial 8,164 patients of both sexes with recent episodes and cerebrovascular events	Supplementation of B-complex vitamins would decrease the incidence of fractures in patients with cerebrovascular disease	Control: N=4075 Placebo treatment: N=4089, B complex vitamins: (folic acid: 2 mg, vitamin B6: 25 mg, vitamin B12 500 µg	Homocysteine levels were lower in the treatment group There was no association between treatment with B vitamins and fracture risk	High
van Wijngaarden et al., 2014²⁵	Randomized, double-blind, placebo-controlled clinical trial. 2,919 Dutch male and female participants, aged ≥ 65 years and high concentrations of homocysteine (12-50 µmol/L), for 2 years	Combined vitamin B9 and B12 supplementation to prevent osteoporotic fractures	Control: daily doses of placebo + 600 IU of vitamin D3 Treatment: daily doses of 500 µg of vitamin B12 and 400 µg of vitamin B9 + 600 IU of vitamin D3	There was no significant reduction in the risk of fractures between groups In the treatment subgroup there was a reduction in fractures among participants over 80 years of age Homocysteine levels decreased significantly in the treatment group	High

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[TFN1] BMD: Bone Mineral Density; MTHFR: Methylene Tetrahydrofolate Reductase; OC: Osteocyclin; TRAP – Tartrate Resistant Acid Phosphatase; BAP: Specific Bone Alkaline Phosphatase; CTx: Carboxyterminal Telopeptide Crosslinking.