Table 1: Studies regarding the association between vitamin B12 and bone health.

Author
Year
Study characteristics
Duration of follow-up (when applicable)
Country
Risk of bias
Population characteristics:
N (% men)
Age (y) ± SD
Vitamin B12 status pmol/L*  
Mean ± SD
Outcome Association type Results*

Dhonukshe-Rutten et al.
2005 [3]
Cohort (3 y)
The Netherlands
High risk
1253 (48%)
75.5 ± 6.6
♀: 289 ± 99
♂: 268 ± 89
Fracture
(verified by physician or radiograph)
β (SE) for association vitB12-fracture (per 50 pmol/L) ♀: −0.09 (0.06)a, 1  
♂: 0.02 (0.08)a, 1

Gjesdal et al. 2007 [24]Cohort (12.6 y)
Norway
Low risk
4761 (45%)
65–67 at baseline
♀: 386.4 ± 372.0
♂: 359.3 ± 276.2
Hip fracture
(verified by hospital discharge diagnoses)
β (SE) for association vitB12-hip fracture (per 50 pmol/L) ♀: −0.03 (0.03)b, 2  
♂: −0.06 (0.05)b, 2

McLean et al. 2008 [25]Cohort (16 y)
USA
Low risk
823 (41%)
75.3 ± 4.9
Deficient (<148):
♀ 9%/♂14.0%
Low (148–257.9):
♀ 24.3%/♂32.5%
Normal (≥258):
♀ 66.7%/♂53.5%
Hip fracture
(verified by review medical records)
β (SE) for association vitB12-hip fracture (per 50 pmol/L) ♀: −0.09 (0.06)c, 1  
♂: −0.09 (0.11)c, 1

Ravaglia et al. 2005 [26]Cohort (4 y)
Italy
Moderate risk
702 (47%)
73.0 ± 6.0
Geometric mean (95% CI)
249.1 (203–272)
Fracture
(verified by review medical records)
β (SE) for association vitB12-fracture (per 50 pmol/L) 0.04 (0.08)d, 2

Bozkurt et al. 2009 [32]Cross-sectional
Turkey
High risk
178 (0%)
53.5 ± 8.0
247.7 ± 85.4BMD: LS, FN
DXA
Logistic regression for FN, LS and FN + LS combined for vitB12 status under the quintile value. β (SE) + P value LS: −2.3 (0.9) P = 0.017
FN: −0.4 (0.9) P = 0.669
LS + FN: 1.8 (0.8) P = 0.045e

Bucciarelli et al. 2010 [33]Cross-sectional
Italy
Moderate risk
446 (0%)
65.1 ± 9.4
(geometric mean ± SD)
399.1 ± 1.6
BMD: FN, LS, TH [DXA, Prodigy, GE, Lunar]β for association vitB12-TH BMD β (SE) (per 50 pmol/L) −0.00105 (0.939)f, 2

Cagnacci et al. 2008 [34]Cohort (5 y)
Italy
Moderate risk
117 (0%)
54.4 ± 0.5
(Mean ± SE)
548.5 ± 40.5
BMD: LS
DXA: Lunar DPX
Regression for vitB12-BMD change β (SE) P value −0.003 (0.012) P = 0.784g

Dhonukshe-Rutten et al.
2003 [35]
Cross-sectional
The Netherlands
Moderate risk
194 (26%)
78.3 ± 5.5
♀ 288 ± 131
♂ 238 ± 95
BMD: whole body
DXA, Lunar DPX-L
Multivariate regression, β for association vitB12-BMD β (95% CI) in women ♀: 12.3·10−5 (0.2·10−5–2.4·10−4)h

Gjesdal et al. 2006 [10]Cross-sectional
Norway
Moderate risk
5329 (43%)
middle aged: 47–50
Older: 71–75
♀ 393.4 ± 235.8
♂ 374.6 ± 230.7
BMD: TH
DXA, Lunar EXPERT-XL
OR (95% CI) for low BMD per category vitB12 status
1: <230 pmol/L
2: 230.0–279.9 pmol/L
3: 280.0–414.9 pmol/L
4: ≥415.0 pmol/L + P for trend
♀: 1: 0.97 (0.68–1.37)
 2: 0.87 (0.63–1.21)
 3: 1.02 (0.82–1.27)
 4: 1.00 (reference)
P for trend
= 0.61
♂: 1.22 (0.82–1.81)
  1.14 (0.80–1.62)
  0.97 (0.74–1.28)
  1.00 (reference)
P for trend
= 0.25i

Golbahar et al. 2004 [9]Cross-sectional
Iran
Moderate risk
271 (0%)
60.8 ± 6.8
(geometric mean ± SD)
339.5 ± 247.6
BMD: FN, LS
DXA, Lunar DPX-L
β (SE) for association vitB12-BMD (per 50 pmol/L) FN: 0.0002 (0.07)2  
LS: 0.0114 (0.14)2

Haliloglu et al. 2010 [36]Cross-sectional
Turkey
Moderate risk
120 (0%)
54.4 ± 1.1
Osteoporotic: 216.0 ± 135.1
Osteopenic: 190.8 ± 97.4
Normal BMD: 251.0 ± 205.8
BMD: LS
DXA, Lunar DPX-L
ANOVA for difference in vitB12 status per BMD group compared to normal BMD group No sign differences in vitB12 status between BMD groups

Krivosikova et al. 2010 [37]Cross-sectional
Slovakia
High risk
272 (0%)
41.3 ± 19.8
273.2 ± 152.7BMD: FN, LS, trochanter, TH
DXA, Lunar DPX-L
Stepwise multivariate linear regression, β for association vitB12-BMD. β (SE) P value (per 50 pmol/L) FN: −2.0 (2.73) j, 2  
LS: −1.15 (1.42) j, 2  
TH: −0.5 (3.03) j, 2

Morris et al. 2005 [7] Cross-sectional
USA
Low risk
1550 (48%)
68
Geometric mean (95% CI) Osteoporosis: 271 (243–302)
Osteopenia: 309 (293–325)
Normal: 310 (297–323)
Serum MMA (nmol/L)
Osteoporosis: 305 (276–337)
Osteopenia: 251 (234–269)
Normal: 241 (212–274)
BMD: Trochanter, intertrochanter, FN, Ward’s triangle, TH DXA, Hologic QDR-1000 OR (95% CI) for mean BMD in relation to quartile categories of vitB12 and MMA status + P for trend. Category medians: Vit B12:
Q1: 2.0 (1.0–3.9)
Q2: 1.3 (0.6–2.7)
Q3: 1.7 (0.8–3.3)
Q4: 1.0 (reference)
P for trend = 0.09
MMA:
1.0
(reference)
3.5
(1.4–8.5)
5.2
(2.0–13.1)
7.2
(3.4–15.2)
P for trend <0.001k  
B12 (pmol/L):
Q1: 182
Q2: 268
Q3: 349
Q4: 495
MMA (nmol/L):
157
206
272
415
Among subjects with vitB12 <220 pmol/L mean BMD increased sign with increasing vitB12 ( )

Naharci et al. 2012 [38]Cross-sectional
Turkey
Moderate risk
264 (100%)
77.0 ± 6.0
26.7% low (<148, group I)
39.1% borderline (148–221, group II)
34.2% normal (>221, group III)
BMD: FN, TH, trochanter, inter-trochanter DXA, hologic QDR-4500 Anova for differences in FN BMD between groups of serum vitB12 Sign differences FN BMD
group I and II ( )
group I and III ( )
group II and III ( )
FN BMD was positively correlated with serum vitB12 ( , )

Ouzzif et al. 2012 [39]Cross-sectional
Morocco
Moderate risk
188 (0%)
57.8 ± 8.5
360.4 ± 149.2
BMD: FN, LS, TH, trochanter DXA, Lunar prodigy Multivariate regression, β for association vitB12-BMD β (SE) (per 50 pmol/L) P valueLS:
−7.85 (0.25)
TH:
−11.65 (0.02)
0L, 2  
  
L, 2

Rumbak et al. 2012 [40]Cross-sectional
Croatia
Low risk
131 (0%)
54.0 ± 4.9
239.6 ± 97.0BMD: FN, LS, TH, radius
DXA, Lunar-prodigy
Stepwise multivariate regression, β for association vitB12-BMD for pre- and postmenopausal women β (SE) P value (per 50 pmol/L) Premenopausal:
LS: −3.39 (8.91) 9m, 2  
FN: 7.45 (10.07) 7m, 2  
TH: −1.36 (7.53) 62m, 2  
Postmenopausal:
LS: 7.45 (8.98) 1m, 2  
FN: 12.20 (8.97) 80m, 2  
TH: 8.81 (8.63) 14m, 2

Stone et al. 2004 [11]Cohort (5.9 y)
USA
Low risk
83 (0%)
71.1 ± 4.4
352 ± 174
BMD: TH, FN (change) DXA, Hologic QDR-1000 t-test for difference in BMD change between low and normal vitB12 status Participants with low vitB12 (≤207 pmol/L) had a more rapid decline in BMD (−1.91%/year) than part. with normal vitB12 (−0.10%/year), P < 0.05

Tucker et al. 2005 [6]Cross-sectional
USA
Low risk
2576 (44%)
58.8 ± 9.5
Distribution per category of plasma vitB12 status
1: ♀ 4.4%/♂4.7% ≤148
2: ♀ 6.9%/♂7.8%
>148–185
3: ♀ 25.4%/♂28.2%
>185–259
4: ♀ 63.3%/♂ 59.3% >259
BMD: FN, LS, TH, Trochanter, Ward
DXA, Lunar DPX-L
Differences in BMD per category of plasma vitB12 level, relative to category 1
♀: FN: no differences
♀: LS: vitB12 in cat 2 (P < 0.10), 3, 4 (P < 0.05) was assoc. with better BMD
♀: TH: vitB12 in cat 3, 4 (P < 0.10) was assoc. with better BMD
♂: FN: vitB12 in cat 2, 3, 4 was assoc. with better BMD (P < 0.05)
♂ LS: no differences
♂ TH: vitB12 in cat 2 (P < 0.10), 3, 4 (P < 0.05) was assoc. with better BMDn

*Serum/plasma vitamin B12 concentrations were converted to pmol/L if applicable, using the following equation: 1 pg/mL = 1 ng/L = 0.738 pmol/L. subsequent outcomes were also converted. Where possible, subgroups were combined. BMD sites: LS: Lumbar Spine, FN: Femoral Neck, TH: Total Hip.
1β(SE) as calculated from data provided by author; 2β (SE) as calculated from presented data.
aadjusted for age, BMI, smoking, recurrent falling; badjusted for age, BMI, smoking, coffee intake, physical activity, vit D use, educational level, estrogen use in women; cadjusted for sex, age, height, weight, estrogen use in women; dadjusted for age, sex, education, osteoporosis drugs, creatinine, tHcy; eadjusted for duration of menopause, smoking, BMI, folic acid levels, tHcy levels; fadjusted for age, BMI, logtHcy, logFolate, creatinine clearance, smoking, alcohol intake; gAdjusted for age, weight, weight change; hadjusted for weight, height, energy intake; iadjusted for smoking, BMI, creatinin, coffee intake, physical activity, use of estrogen therapy; jadjusted for age, folate, tHcy, PTH, CTx, Ca, Cr; kAdjusted for age, sex, ethnicity, BMI, smoking, physical activity, creatinin, alcohol, coffee, energy, calcium, vitamin D zinc intake; Ladjusted for age, BMI, tHcy and folate; madjusted for Age, BMI, smoking, alcohol, physical activity, tHcy, Folate; nadjusted for energy, calcium, vitamin D intake, BMI, height, smoking, age, physical activity, calcium supplement, vitamin D supplement, alcohol, osteoporosis medication, season of measurement.