Table 2: Studies regarding the association between folate and bone health.

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

Gjesdal et al. 2007 [24]Cohort (12.6 y)
Norway
Low risk
4761 (45%)
65–67 at baseline
♀ 6.0 ± 3.5
♂ 5.2 ± 2.7
Hip fracture
(verified by hospital discharge diagnoses)
HR for hip fracture according to folate status
1: <2.9
2: 2.9–3.8
3: 3.9–6.5
4: ≥6.6
♀: 1: 2.40 (1.50–3.84)
 2: 1.15 (0.68–1.94)
 3: 1.02 (0.68–1.54)
 4: 1.00 (reference)a
♂: 1.00 (0.48–2.12)
 0.80 (0.39–1.62)
 0.81 (0.45–1.46)
 1.00 (reference)a

McLean et al. 2008 [25]Cohort (16 y)
USA
Low risk
960 (41%)
75.3 ± 4.9
Not shownHip fracture
(verified by review medical records)
HR for hip fracture according to folate status
Normal: ≥11 Low: 7–10.9 Deficient: <7
Normal: 1.00 (reference)
Low: 0.76 (0.43, 1.32)
Deficient: 1.38 (0.91, 2.09)b

Ravaglia et al. 2005 [26]Cohort (4 y)
Italy
Moderate risk
702 (47%)
73.0 ± 6.0
11.7 (9.0–12.2)
mean (95% CI)
Fracture
(verified by review medical records)
OR (95% CI) for risk of fracture at follow-up for each increment of 1 sd in the log-transformed serum folate value 0.83 (0.59–1.19)c

Baines et al. 2007 [41]Cross-sectional
Great Britain
High risk
328 (0%)
67.5 (40–85)
mean (range)
Osteoporosis:
8.1 ± 8.7#  
Osteopenia:
10.2 ± 4.6
Normal: 9.4 ± 6.3
BMD: os calcis/ heel bone PIXI, GE Lunar ANOVA for difference between the normal, osteopenia and osteoporosis group FA status was significantly different between osteroporotic and osteopenic group
(P = 0.049)

Bozkurt et al. 2009 [32]Cross-sectional
Turkey
High risk
178 (0%)
53.5 ± 8.0
24.9 ± 7.9
BMD: FN, LS
DXA
Logistic regression for FN, LS and FN + LS combined. β (SE) + P value for assoc. BMD-folate status under the median value LS: −0.2 (0.2) P = 0.417
FN: −0.04 (0.2) P = 0.835
LS + FN: −0.03 (0.2)
P = 0.896d

Bucciarelli et al. 2010 [33]Cross-sectional
Italy
Moderate risk
446 (0%)
65.1 ± 9.4
(geometric mean ± SD)
3.8 ± 1.6
BMD: FN, LS, TH DXA, Prodigy, GE, Lunar β for association folate-TH BMD β (SE) 0.004 (0.018)e, 2

Cagnacci et al. 2008 [34]Cohort (5 y)
Italy
Moderate risk
117 (0%)
54.4 ± 0.5
(Mean ± SE)
20.6 ± 1.4
BMD: LS
DXA: Lunar DPX
Regression analysis for folate-BMD change β (SE) + P value 1.602 (0.803) P = 0.048f

Cagnacci et al. 2003 [8]Cross-sectional
Italy
Moderate risk
161 (0%)
53.3 ± 1.04
(Mean ± SE)
21.5 ± 4.3
BMD: LS
DXA: Lunar DPX
Regression analysis, r (P value) for association folate-BMDr = 0.254 (P < 0.002)

Gjesdal et al. 2006 [10] Cross-sectional
Norway
Moderate risk
5329 (43%)
middle aged:
47–50
Older: 71–75
♀ 8.9 ± 7.1
♂ 7.3 ± 4.6
BMD: TH DXA, Lunar EXPERT-XL OR (95% CI) for low BMD per category folate status:
1: FA < 3.8 nmol/L
2: FA 3.8–4.9 nmol/L
3: FA 5.0–8.4 nmol/L
4: FA ≥ 8.5 nmol/L + P for trend
Multivariate regression for folate-BMD β (SE) (per 50 nmol/L)
♀: 1: 1.55 (1.07–2.23)
 2: 1.18 (0.86–1.63)
 3: 1.24 (0.99–1.56)
 4: 1.00 (reference)
P for trend = 0.02
♂: 0.81 (0.53–1.24)
 0.96 (0.67–1.38)
 1.15 (0.87–1.53)
 1.00 (reference)
P for trend = 0.26g  
Elderly women: β = 0.05 (0.02)g, 2

Golbahar et al. 2004 [9]Cross-sectional
Iran
Moderate risk
271 (0%)
60.8 ± 6.8
(geometric mean ± SD)
11.6 ± 6.5
BMD: FN, LS DXA, Lunar DPX-L β for association folate-BMD β (SE) FN: 0.008 (0.019)h, 2  
LS: 0.010 (0.018)i, 2

Haliloglu et al. 2010 [36]Cross-sectional
Turkey
Moderate risk
120 (0%)
54.4 ± 1.1
Osteoporotic:
12.2 ± 6.3
Osteopenic:
15.4 ± 7.4
Normal: 15.8 ± 8.3
BMD: LS
DXA, Lunar DPX-L
ANOVA for difference in folate status per BMD group (osteoporotic, osteopenic, compared to normal BMD group) No significant differences in folate status between BMD groups

Krivosikova et al. 2010 [37]Cross-sectional Slovakia
High risk
272 (0%)
41.3 ± 19.8
23.8 ± 9.6BMD: FN, LS, trochanter, TH
DXA, Lunar DPX-L
Stepwise multivariate linear regression, β for association folate-BMD.
β (SE) P value
FN: −0.028 (0.054) P = 0.606 j, 2  
LS: −0.001 (0.067) P = 0.988 j, 2  
TH: −0.032 (0.060) P = 0.595 j, 2

Morris et al. 2005 [7]Cross-sectional
USA
Low risk
1550 (47%)
68
Osteoporosis: 17.2 (15.4–19.2)
Osteopenia: 17.2 (16.0–18.5)
Normal: 16.7 (15.3–18.3) Geometric mean (95% CI)
BMD: Trochanter, intertrochanter, FN, Ward’s triangle, TH DXA, Hologic QDR-1000 OR (95% CI) for mean BMD in relation to quartile categories of folate status + P for trend
Category median (nmol/L):
Q1: 8.0
Q2: 12.4
Q3: 20.3
Q4: 38.9
Q1: 1.1
Q2: 1.1
Q3: 1.5
Q4: 1.0
P for trend
(0.5–2.3)
(0.0.5–2.9)
(0.7–3.4)
(reference)
= 0.83k

Naharci et al. 2012 [38]Cross-sectional
Turkey
Moderate risk
264 (100%)
77.0 ± 6.0
low (<7.0, group I): 0.0%
borderline (7.0–10.9, group II): 9.2%
normal (>10.9, group III): 90.8%
BMD: FN, TH, trochanter, intertrochanter
DXA, hologic QDR-4500
Independent sample t-test for differences in FN BMD between group II and III of serum folate No significant differences in BMD (all sites) between group II and III of folate status

Ouzzif et al. 2012 [39]Cross-sectional
Morocco
Moderate risk
188 (0%)
57.8 ± 8.5
15.6 ± 6.8BMD: FN, LS, TH, trochanter DXA, Lunar prodigy Multivariate regression, β for association folate-BMD β (SE) + P value LS: 0.007 (0.002) P = 0.808L  
TH: 0.006 (0.001) P = 0.834L

Rumbak et al. 2012 [40]Cross-sectional
Croatia
Low risk
131 (0%)
54.0 ± 4.9
22.4 ± 7.5BMD: FN, LS, TH, radius
DXA, Lunar-prodigy
Stepwise multivariate regression, β for association folate-BMD
β + P value
Premenopausal:
LS: 3.31 (4.73) P = 0.490m, 2  
FN: 1.32 (4.90) P = 0.791m, 2  
TH: 2.87 (4.35) P = 0.516m, 2  
Postmenopausal:
LS: −3.75 (3.47) P = 0.284m, 2  
FN: −1.32 (3.15) P = 0.679m, 2  
TH: 0.66 (3.89) P = 0.862m, 2

*Serum/plasma folate concentrations were converted to nmol/L if applicable, using the following equation: 1 ng/ml = 2.266 nmol/L. Subsequent outcomes were also converted. Where possible, subgroups were combined. BMD sites—LS: Lumbar Spine, FN: Femoral Neck, TH: Total Hip #data presented in article as μmol/L, this is presumably a typing error and should be nmol/L.
1β (SE) as calculated from data provided by author; 2β (SE) as calculated from presented data.
aadjusted for age, BMI, smoking, coffee intake, physical activity, vit D use, educational level, estrogen use in women; badjusted for sex, age, height, weight, estrogen use in women; cadjusted for age, gender, education, osteoporosis drug, serum creatinine, tHcy; dAdjusted for duration of menopause, smoking, BMI, B12, tHcy; eadjusted for age, BMI, logtHcy, logB12, creatinine clearance, smoking, alcohol intake;
fAdjusted for age, weight, weight change; gAdjusted for smoking, BMI, creatinin, coffee intake, physical activity, use of estrogen therapy; hadjusted for age, BMI, alkaline phosphatase; iadjusted for years since menopause, BMI, alkaline phosphatase, creatinine; jadjusted for age, B12, 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, B12; madjusted for Age, BMI, smoking, alcohol, physical activity, tHcy, B12.