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 type | Results | ||
|---|---|---|---|---|---|---|---|---|
| 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 |
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|
| ||||||||
| 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 |
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|
| ||||||||
| 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 |
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| 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 tHcy | Normal 1.00 High 1.69 |
(reference) (1.12–2.55)g |
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| 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 | ||
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| ||||||||
| 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 |
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| 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-BMD | β = −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 |
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| 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 |
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| 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 |
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| ||||||||
| 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) | ||
|
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| 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 |
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| 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 |
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| Ouzzif et al. 2012 [39] | Cross-sectional Morocco Moderate risk |
188 (0%) 57.8 ± 8.5 |
12.4 ± 4.1 | BMD: 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 |
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| 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 |
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| Rumbak et al. 2012 [40] | Cross-sectional Croatia Low risk |
131 (0%) 54.0 ± 4.9 |
9.9 ± 2.0 | BMD: 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 |
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| 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, 2 β (SE) as calculated from presented data, 3 β (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.