Table 3: Studies regarding the association between homocysteine and bone health.

Author
Year
Study characteristics
Duration of follow-up (when applicable)
Country
Risk of bias
Population characteristics:
N (%men)
Age (y) ± SD
Homocysteine status (μmol/L)
Mean ± SD
Outcome Association typeResults

Dhonukshe-Rutten et al. 2005 [3]Cohort (3y)
The Netherlands
High risk
1253 (48%)
75.5 ± 6.6
geometric mean (10–90 percentile)
♀: 13.0 (8.6–19.7)
♂: 14.9 (10.2–22.8)
Fracture (verified by physician or radiograph)β (SE) for association tHcy-fracture ♀: 0.07 (0.05)a, 2  
♂: 0.11 (0.05)a, 2

Enneman et al. 2012 [30]Cohort (7 y)
The Netherlands
Moderate risk
503 (0%)
68.5 (61.3–74.9)
Median (range)
Median (range)
9.3 (3.5–29.7)
Fracture (verified by physician)β (SE) for association tHcy-fracture 0.05 (0.02)b, 2

Gerdhem et al. 2007 [29]Cohort (7 y)
Sweden
Low risk
996 (0%)
75
Median (IQR)
14.1 (11.6–17.3)
Hip fracture (verified by radiograph)β (SE) for association tHcy-hip fracture 0.07 (0.03)c, 2

Gjesdal et al. 2007 [24]Cohort (12.6 y)
Norway
Low risk
4761 (45%)
65–67 at baseline
♀: 11.6 ± 4.2
♂: 13.1 ± 5.8
Hip fracture (verified by hospital discharge diagnoses)β (SE) for association tHcy-hip fracture ♀: 0.05 (0.02)d, 2  
♂: 0.03 (0.03)d, 2

Leboff et al. 2009 [28]
Nested case-control
USA
Moderate risk
800 (0%)
70.8 ± 6.2
11.2 ± 4.1
Hip fracture (verified by radiograph)β (SE) for association tHcy-Hip fracture 0.07 (0.03)e, 2

HR (95% CI) for hip fracture risk by quartiles of tHcy. Mean tHcy per quartile:
McLean et al. 2004 [4] Cohort (♀ 15 y; ♂12.3 y)
USA
Moderate risk
1999 (41%)
70.0 ± 7.0
♀: 12.1 ± 5.3
♂: 13.4 ± 9.1
Hip fracture (verified by review medical records)♀:
Q1: 7.6 ± 1.0
Q2: 9.9 ± 0.7
Q3: 12.2 ± 0.7
Q4: 18.6 ± 6.4
♂:
8.5 ± 0.9
11.0 ± 0.6
13.4 ± 0.9
20.8 ± 15.7
♀: 1: 1.00 (reference)
 2: 0.78 (0.45–1.33)
 3: 1.07 (0.64–1.78)
 4: 1.92 (1.18–3.10)
♂: 1.00 (reference)
 1.57 (0.54–5.14)
 2.07 (0.70–6.09)
 3.84 (1.38–10.70)
HR (95% CI) for each increase of 1 SD in log-transformed tHcy concentration ♀/♂ Test for trend: P < 0.01
♂ HR per SD 1.59 (1.31–1.94)f  
♀ HR per SD 1.26 (1.08–1.47)f

McLean et al. 2008 [25]Cohort (16 y)
USA
Low risk
979 (41%)
75.3 ± 4.9
73.7% normal (≤14 μmol/l)
26.3% high (>14)
Hip fracture (verified by review medical records) HR (95% CI) for high plasma tHcy (≥14 μmol/L) versus normal tHcyNormal 1.00
High 1.69
(reference)
(1.12–2.55)g

Van Meurs et al. 2004 [5]Cohort (4.7 y)
The Netherlands
High risk
2406 (47%)
73.9 ± 7.8
14.3 ± 5.8
Fracture (verified by physician) RR (95% CI) for fracture for each increment of 1 SD in the natural log-transformed tHcy value. 1.4 (1.2–1.6)h

Périer et al. 2007 [27]Cohort (10 y)
France
Moderate risk
671 (0%)
61.6 ± 8.4
10.6 ± 3.5 Fracture (verified by radiograph or surgical report)β (SE) for association tHcy-fracture 0.02 (0.02)i, 3

Ravaglia et al. 2005 [26]Cohort (4 y)
Italy
Moderate risk
702 (47%)
73.0 ± 6.0
Geometric mean (95% CI)
12.7 (11.3–15.1)
Fracture (verified by review medical records)β (SE) for association tHcy-fracture 0.09 (0.05)j, 2

Zhu et al. 2009 [31]Cohort (5 y)
Australia
Moderate risk
1213 (0%)
75.2 ± 2.7
12.1 ± 4.6 Fracture (verified by radiograph)β (SE) for association tHcy-fracture −0.002 (0.006)k, 2

Baines et al. 2007 [41]Cross-sectional
Great Britain
High risk
328 (0%)
67.5 (40–85)
mean (range)
12.3 ± 5.4
BMD: os calcis/heel bone PIXI, GELunar Stepwise multivariate linear regression β (SE) + P value for association log tHcy-BMD −1.548 (0.607) P = 0.011L

Bozkurt et al. 2009 [32]Cross-sectional
Turkey
High risk
178 (0%)
53.5 ± 8.0
10.4 ± 3.0#BMD: FN/LS DXA Logistic regression for FN, LS and FN + LS combined. β (SE) + P value for association hcy level under the median value-BMD LS: −0.8 (0.5) P = 0.140
FN: −0.5 (0.6) P = 0.408
LS + FN: −1.3 (0.6) P = 0.032m

Bucciarelli et al. 2010 [33]Cross-sectional
Italy
Moderate risk
446 (0%)
65.1 ± 9.4
(geometric mean ± SD)
10.6 ± 1.3
BMD: FN, LS, TH DXA, Prodigy, GE, Lunar Multivariate linear regression β for association log tHcy-total femur BMD. β (SE) P value −0.050 (0.025) P = 0.048n, 2

Cagnacci et al. 2008 [34]Cohort
Italy
Moderate risk
117 (0%)
54.4 ± 0.5
(Mean ± SE)
10.7 ± 0.5
BMD: LS
DXA: Lunar DPX
Regression analysis for Hcy-BMD change β (SE) + P value −0.825 (1.09) P = 0.449o

Cagnacci et al. 2003 [8]Cross-sectional
Italy
Moderate risk
161 (0%)
53.3 ± 1.0
10.5 ± 0.9
BMD: LS
DXA: Lunar DPX
Regression analysis, β for association Hcy-BMDβ = −0.002p, 1

Gerdhem et al. 2007 [29]Cohort (cross sect data)
Sweden
Low risk
996 (0%)
75
Median (IQR)
14.1 (11.6–17.3)
BMD: FN, LS, TH
DXA: Lunar DPX-L
t-test for difference in BMD (P value)
between highest quartile of hcy versus all others
FN: Q4 versus
LS: Q4 versus
TH: Q4 versus
Q1–3: P = 0.032
Q1–3: P = 0.821
Q1–3: P = 0.001

Gjesdal et al. 2006 [10] Cross-sectional
Norway
Moderate risk
5329 (43%)
middle aged:
47–50
Older: 71–75
♀: 10.2 ± 4.5
♂: 11.8 ± 3.9
BMD: TH
DXA, Lunar EXPERT-XL
Multivariate regression, β for association tHcy-BMD (P value) for middle aged and elderly women. (Data men not shown)
OR (95% CI) for low BMD per category tHcy status + P for trend:
Mid. aged women: β = 0.004 (P < 0.001)
elderly women: β = 0.003 (P < 0.001)q  
1: <9.0 μmol/L
2: 9.0–11.9 μmol/L
3: 12.0–14.9 μmol/L
4: ≥15 μmol/L
♀: 1: 1.00 (reference)
 2: 1.14 (0.90–1.44)
 3: 1.30 (0.95–1.79)
 4: 2.19 (1.48–3.25)
P for trend <0.001
♂: 1.00 (reference)
 1.01 (0.74–1.37)
 1.12 (0.79–1.60)
 1.02 (0.66–1.56)
P for trend = 0.72q

Golbahar et al. 2004 [9]Cross-sectional
Iran
Moderate risk
271 (0%)
60.8 ± 6.8
geometric mean (95% CI)
13.7 (7–14)
BMD: FN, LS DXA, Lunar DPX-L β for association tHcy-BMD β (SE) FN: −0.012 (0.023)2  
LS: −0.010 (0.024)2

Haliloglu et al. 2010 [36]Cross-sectional
Turkey
Moderate risk
120 (0%)
54.4 ± 1.1
Osteoporotic: 15.0 ± 4.6
Osteopenic: 14.2 ± 3.7
Normal: 11.2 ± 2.6
BMD: LS
DXA, Lunar DPX-L
ANOVA for difference in tHcy status per BMD group
tHcy was sign. higher in the osteoporotic group versus normal group (P < 0.05)

Krivosikova et al. 2010 [37]Cross-sectional Slovakia
High risk
272 (0%)
41.3 ± 19.8
(μmol/L)
14.6 ± 5.5
BMD: FN, LS, trochanter, TH
DXA, Lunar DPX-L
Stepwise multivariate linear regression, β for association tHcy-BMD. β (SE) P value
FN: −0.093 (0.06) P = 0.100r, 2  
LS: 0.003 (0.07) P = 0.965r, 2  
TH: −0.134 (0.06) P = 0.033r, 2

Morris et al. 2005 [7]Cross-sectional
USA
Low risk
1550 (47%)
68
Osteoporosis:
11.5 (10.3–12.7)
Osteopenia: 10.2 (9.5–10.8)
Normal: 10.0 (9.6–10.5)
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 tHcy status + P for trend
Category median (μmol/L):
Q1: 6.9
Q2: 8.9
Q3: 10.8
Q4: 14.8
Q1: 1.0 (reference)
Q2: 0.9 (0.4–1.9)
Q3: 2.0 (0.7–5.1)
Q4: 2.0 (0.8–4.9)
P for trend = 0.09 sDose response analysis: subjects with tHcy level >20 μmol/L had sign lower BMD than subj with tHcy level <10 μmol/L

Ouzzif et al. 2012 [39]Cross-sectional
Morocco
Moderate risk
188 (0%)
57.8 ± 8.5
12.4 ± 4.1BMD: FN, LS, TH, trochanter DXA, Lunar prodigy Multivariate regression, β for association tHcy-BMD β (SE) + P value LS: −0.089 (0.003) P = 0.200t  
TH: −0.155 (0.002) P = 0.021t

Périer et al. 2007 [27]Cohort (cross-sect data)
France
Moderate risk
671 (0%)
61.6 ± 8.4
10.6 ± 3.5
BMD: FN, LS,TH DXA, Hologic QDR-2000 β for association tHcy-BMD β (SE) LS: −0.000065 (0.004)
FN: −0.006 (0.004)
TH: −0.006 (0.004)2

Rumbak et al. 2012 [40]Cross-sectional
Croatia
Low risk
131 (0%)
54.0 ± 4.9
9.9 ± 2.0BMD: FN, LS, TH, radius
DXA, Lunar-prodigy
Stepwise multivariate regression, β for association tHcy-BMD. β (SE) for premenopausal and postmenopausal women Premenopausal womenu, 2:   
LS: 0.20 (0.14) P = 0.176
FN: 0.17 (0.15) P = 0.253
TH: 0.20 (0.14) P = 0.170
Postmenopausal womenu, 2:
LS: 0.12 (0.15) P = 0.439
FN: 0.20 (0.15) P = 0.181
TH: 0.12 (0.14) P = 0.391

Zhu et al. 2009 [31] Cohort (5 y)
Australia
Moderate risk
1213 (0%)
75.2 ± 2.7
12.1 ± 4.6 BMD: TH DXA, Hologic Acclaim 4500A Change in hip BMD from 1 to 5 years per tertile of tHcy (μmol/L) ANOVA Tertile 1 and 3 differ significantly (P < 0.05)

BMD sites—LS: Lumbar Spine, FN: Femoral Neck #data presented in article as nmol/L, this is presumably a typing error and should be μmol/L.
1data as provided by author on our request, 2β (SE) as calculated from presented data, 3β (SE) as calculated from data provided by author on our request.
aadjusted for age, BMI, smoking status, recurrent falling, serum creatinine; badjusted for age and BMI; cadjusted for serum creatinine (natural log), B12 level, folic acid level, BMI, smoking, walking speed, BMD, LnPTH; dadjusted for age, BMI, smoking, coffee intake, physical activity, vit D use, educational level, estrogen use in women; ecase-control matched for age and ethnicity. Adjusted for BMI, parental history of hip fracture, treated diabetes, alcohol use, smoking, history of stroke, total calcium intake; fadjusted for sex, age, height, weight, smoking status, caffeine intake, alcohol intake, education level, estrogen use in women; gadjusted for sex, age, height, weight, estrogen use in women; hadjusted for age, sex, BMI, changes in BMI before entry in the study, smoking, fall history, serum creatinine; iadjusted for age, prevalent fractures, BMD, calcium intake, physical activity, vitamin D level, creatinine, albumin, estradiol; jadjusted for age, gender, education, serum creatinine, osteoporosis drugs; kadjusted for age, weight, hip BMD, prevalent fracture, calcium treatment; Ladjusted for weight, cysteine, smoking and height; mAdjusted for duration of menopause, smoking, BMI, folic acid levels, homocysteine levels; nadjusted for age, BMI, logFolate, logB12, creatinine clearance; oAdjusted for age, weight, weight change; pAdjusted for BMI, smoking, age; qAdjusted for smoking, BMI, creatinine, coffee intake, physical activity, use of estrogen therapy; radjusted for age, B12, folate, PTH, CTx, Ca, Cr; sadjusted for age, sex, ethnicity, BMI, smoking, physical activity, creatinin, alcohol, coffee, energy, calcium, vitamin D zinc intake; tadjusted for age, BMI, folate, B12; uadjusted for age, BMI, smoking, alcohol intake, physical activity, duration of menopause, HRT, levels of hcy, vitB12 and folate.