2. The Relationship Ship between Vitamin K Status and OA
2.1. Case-Control Studies
2.2. Cross-Sectional Studies
2.3. Prospective Studies
2.4. Clinical Trial
3. Mechanism of Action
Conflicts of Interest
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|Roberts et al. 1996 ||Patients with femoral neck fracture (n = 13): 10 women, median age 80 years; 3 men, median age 85 years. |
OA patients (n = 16): 10 women, median age 71 years; 6 men, median age 64 years.
Healthy volunteers (n = 25): 16 women and 9 men, median age 77 years.
Blood was sampled from the patients before and after surgery.
Serum vitamin K1 measured by HPLC.
|Vitamin K1: ↓ in patients with femoral neck fracture and OA vs. normal controls; ↓ after surgery. |
Carboxylated and undercarboxylated osteocalcin: ~ between case and control.
|Silaghi et al. 2012 ||Non-inflammatory arthritis group: n = 17, median age 55 years, patients with OA or chondrocalcinosis|
Inflammatory arthritis group: n = 9, median age 55 years, patients with juvenile idiopathic arthritis, ankylosing spondylitis
Control: n = 30, median age 42 years, no radiographic evidence of arthritis
Uncarboxylated MGP measured by ELISA
|Serum uncarboxylated MGP: ↑ in the controls vs. patients with arthritis; ↑ in the non-inflammatory arthritis group vs. inflammatory arthritis group.|
Synovial uncarboxylated MGP: ↑ in the inflammatory arthritis group vs. non-inflammatory arthritis group
Synovial/serum uncarboxylated MGP ratio: ↑ in the inflammatory group vs. non-inflammatory group.
|Rafael et al. 2014 ||OA samples from patients undergoing total knee replacement surgery. |
Control samples from the autopsy of subjects with no history of joint disease.
|Undercarboxylated GRP: ↑ in the OA cartilage matrix and synovial membrane vs. to carboxylated one. |
Carboxylated MGP: ↑ in the control cartilage matrix and synovial membrane vs. undercarboxylated ones.
|Bing and Feng 2015 ||Case: 178 knee OA patients, aged 62.8 ± 7.4 years, 114 women: 64 men|
Control: 160 healthy outpatients in a hospital, aged 63.2 ± 8 years, 94 women: 66 men
OA assessment: knee radiographs with KL criteria (at least ≥ 2 at one knee to be selected as cases)
Uncarboxylated MGP measured using ELISA
|Serum uncarboxylated MGP: ↓ in the OA patients vs. control. |
Synovial fluid uncarboxylated MGP level correlated negatively with the disease severity among the OA patients.
|El-Brashy et al. 2016 ||Case: 40 knee OA patients (36 women: 10 men), age 50.4 ± 4.9 years, KL grade 2 or less|
Control 20 healthy individuals (85 women: 15 men), age 48.9 ± 4.6 years,
Plasma phylloquinone level was measured using ELISA
OA assessed using pain scale, The Western Ontario McMaster Scale (WOMAC), Thomas Grading Score and musculoskeletal ultrasound
|Plasma vitamin K: ↓ in knee OA patients vs. control |
WOMAC score: ↑ in patients with vitamin K deficiency vs those who were sufficient.
A significant positive correlation was found between plasma vitamin K level and medial cartilage thickness.
|Neogi et al. 2006 ||Framingham Offspring Study. |
Subjects: n = 672, 53% women. Mean age 66 years
OA assessed using Framingham OA atlas.
Phylloquinone level assessed using HPLC.
|↓ hand OA and large osteophyte for subjects with the Q4 (1.81–21.5 nmol/L) of phylloquinone level vs. Q2 (0.59–1.02 nmol/L) & Q1 (0.05–0.58 nmol/L). |
↓ joint space narrowing for hand OA in Q4 vs. Q1.
A threshold effect of 1 nmol/L was observed, in which ↓ OA prevalence after that level.
Knee joint OA not associated with phylloquinone level
|Oka et al. 2009 ||Research on Osteoarthritis Against Disease (ROAD) study. |
Subjects: 719 Japanese subjects, 62.4% women. Mean age 72.1 ± 6.3 years for men, 72.0 ± 7 yrs for women.
OA assessed through radiographs using KL grade.
Vitamin K intake assessed through Brief Dietary History Questionnaire
|Vitamin K intake was associated with ↓ OA grade ≥ 2 (OR 0.75 95% CI 0.63–0.89) or ≥ 3 (OR 0.67 95% CI 0.53–0.84). |
Based on sex, the relationship of OA grade ≥ 2 remained for men (OR 0.76 95% CI 0.59–0.95) and women (OR 0.74 95% CI 0.58–0.96). For women, the relationship of OA grade ≥ 3 (OR 0.61 95% CI 0.45–0.81) was associated with vitamin K intake.
|Misra et al. 2011 ||376 subjects participated in a randomized controlled trial on the effects of vitamin K supplementation on bone and vascular health. 59% women, age 71 ± 5.5 years.||No association between serum MGP levels and hand OA.|
Homozygote rs1800802 minor allele (GG) was associated with a lower risk of hand OA vs. having 1 major allele at this locus (OR 0.56, 95% CI 0.32–0.99).
The same allele was associated with a lower risk of joint space narrowing (OR 0.25, 95% CI 0.11–0.58) and osteophyte formation (OR 0.31, 95% CI 0.17–0.58).
Homozygote rs4236 major allele (TT) was associated with a lower risk of joint space narrowing compared to genotypes with at least one minor allele (OR 0.52, 95% CI 0.35–0.78).
|Naito et al. 2012 ||25 patients with KL grade 3/4 for bilateral knee OA (age: 76 + 7.8 years, BMI; 24.9 + 4.7) were recruited. |
Serum undercarboxylated osteocalcin was measured by ELISA.
|Serum undercarboxylated osteocalcin: marginal ↑ increase in patients with KL grade 6/7/8.|
Positive correlation between undercarboxylated osteocalcin and bone metabolism markers (serum N-terminal telopeptide and bone alkaline phosphatase) and synovitis marker (serum hyaluronan), but not with cartilage metabolism markers (urinary CTX-II and C-terminal type II procollagen peptide).
|Ishii et al. 2013 ||58 bones from patients (13 men; 45 women) undergoing (aged 73 ± 8 years) total knee arthroplasty (all grade 4 OA) were collected. Vitamin K2 in the medial and lateral femoral and tibial condyles were compared. |
Vitamin K2 was analysed using HPLC.
|↑ Vitamin K2 in the lateral femoral and tibial condyles than the medial condyles; ↑ in the femoral lateral/medial condyles than the tibial lateral/medial condyles but only the lateral parts were significant. The difference in age and sex was not significant.|
|Muraki et al. 2014 ||Research on Osteoarthritis/Osteoporosis Against Disability Study (ROAD)|
Subjects: 827 subjects (305 men, 522 women), mean age 69.2 ± 9.3 years.
A knee OA computer-aided diagnostic system was used to analyse minimum joint space width (mJSW) and osteophyte area.
Vitamin K intake (previous month) assessed via Brief Dietary History Questionnaire
|Vitamin K intake was significantly associated with mJSW but not osteophyte area.|
In women, vitamin K, B1, B2, B6, and C intakes were associated with mJSW, after adjusting for age, BMI and total energy.
In women, vitamin E, B1, B2, niacin, and B6 were associated with osteophyte area.
|Shea et al. 2015 ||791 community-dwelling elderly (mean age 74+3 years, BMI 27.7 + 4.8, 67% women) from Healthy, Aging and Body Composition Study (Health ABC). 40% African Americans and 60% Caucasians. Median follow up period of 37 months. |
OA assessed via Magnetic resonance imaging on both knees
Plasma phylloquinone measured using reversed-phase HPLC
Vitamin K intake assessed via The Health ABC food frequency questionnaire
MGP assessed via ELISA
|↑ plasma dephosphorylated uncarboxylated MGP (highest vs lowest quartiles) was associated with ↑ risk of meniscus damage (OR: 1.6, 95%CI 1.1–2.3), osteophytes (OR: 1.7, 95%CI 1.1–2.5), bone marrow lesions (OR: 1.9, 95%CI 1.3–2.8) and subarticular cyst (OR: 1.5, 95%CI 1.0–2.1). |
African Americans in the lowest uncarboxylated MGP quartile had the highest risk of having articular damage.
Caucasians with non-detectable plasma vitamin K were more likely to have meniscal damage.
|Shea et al. 2019 ||Health ABC: n = 1323 (635 men) for plasma phylloquinone HPLC measurement; n = 716 for uncarboxylated MGP measurement. Age 74.2 ± 2.8 years, 40% black/60% white.|
Mobility limitation defined as 2 consecutive semiannual reports of difficulties either walking 1/4 miles or climbing 10 steps.
Mobility disability defined as 2 consecutive semiannual reports of huge difficulties/inability to walk 1/4 miles.
|Subjects with circulating vitamin K level < 0.5 nmol/L had more risk for mobility limitation (OR: 1.49 (96% CI 1.04–2.13)) and disability (OR: 1.95 (96% CI 1.08–3.54)) compared to those with > 1.0 nmol/L uncarboxylated MGP was not associated with both variables.|
|Misra et al. 2013 ||1180 subjects from Multicenter Osteoarthritis (MOST) study, 62% women, mean age 62 + 8 years.|
Knee radiographs or MRI scan obtained at baseline and 30 months later.
Plasma phylloquinone measured at baseline using HPLC.
New incidence of OA referred to KL grade 0/1 to > 2, cartilage lesion based on Whole-Organ Magnetic Resonance Imaging Score from 0 > 1 and osteophytes from 0/1 to >2.
|Subclinical vitamin K deficiency (9.2% of the overall population) was associated with incident radiographic knee OA (RR: 1.56 95% CI 1.08–2.25) cartilage lesion (RR: 2.39 95% CI 1.05–5.40) but not with osteophytes (RR 2.35 95%CI 0.54–10.13). It was also associated with OA at one or both knees (RR 1.33 95% CI 1.01–1.75 and RR 2.12 95% CI 1.06–4.24).|
|Shea et al. 2015 ||Cross-sectional and longitudinal studies. 791 community-dwelling elderly (mean age 74 + 3 years, BMI 27.7 + 4.8, 67% W) From Healthy, Aging and Body Composition Study (Health ABC). 40% African Americans and 60% Caucasians. Median follow up period of 37 months. |
OA assessed using magnetic resonance imaging on both knees.
Vitamin K assessed using plasma phylloquinone measured using reversed-phase HPLC.
Dietary intake assessed using the Health ABC food frequency questionnaire.
MGP assessed using ELISA.
|Non-detectable plasma vitamin K level (<0.2 nmol/L) at baseline predicted articular cartilage (OR: 1.7, 95%CI 1.0–3.0) and meniscus damage (OR 2.6, 95%CI 1.3–5.2) after three years, compared to those with sufficient vitamin K. |
Plasma uncarboxylated MGP did not predict knee pain at baseline.
|El-Brashy et al. 2016 ||A case-control study with 12 months longitudinal follow up.|
Case: 40 knee OA patients (36 women: 10 men), age 50.4 ± 4.9 years, KL grade 2 or less
Control 20 healthy individuals (85 women: 15 men), age 48.9 ± 4.6 years
Plasma phylloquinone level was measured using ELISA.
OA assessed using pain scale, The Western Ontario McMaster Scale (WOMAC), Thomas Grading Score and musculoskeletal ultrasound.
|↑ WOMAC score and pain scale of patients with deficiency vs. those with sufficient level.|
↓ cartilage thickness at medial, lateral and sulcus condyles in patients with vitamin K deficiency.
The same observation was obtained for Thomas score at the medial compartment and total score.
Vitamin K deficiency (0.5 nmol/L) among the patients was associated with radiographic OA progression (RR: 2.08, 95% CI 1.30–3.32).
The best cut-off for vitamin K on radiographic OA progression was 1.74 nmol/L, on ultrasound was 1.28 nmol/L.
|Shea et al. 2018 ||Two prospective cohort studies: Health, ABC and Osteoarthritis Initiative (OAI).|
In Health ABC: n = 1069, 60% women, aged 75 ± 3 years.
Plasma phylloquinone and 25-hydroxyvitamin D were determined.
Physical function: short physical performance battery and usual 20-meter gait speed.
In OAI: n = 4475, 58% women, aged 61 ± 9 yrs.
Vitamin K and D intakes were determined using the Block Brief 2000 food frequency questionnaire.
Physical function: 20-meter gait speed and chair stand completion time.
Follow-up period for both: 4–5 years.
|In Health ABC, adequate circulating K (≥ 1 nmol/L) and D (≥ 50 nmol/L) predicted better physical performance battery scores and gait speed on follow up.|
Changes in physical performance score were not associated with vitamin D status. Both variables showed no correlation with gait speed.
In OAI, adequate vitamin K (≥ 90 µg/day for women or 120 µg/day for men) and D intake (≥ 600 IU for age < 70 years, ≥ 800 IU for age ≥ 70 years) were associated with overall 20-m gait speed and chair stand completion time on follow up, but not 400-meter walk time.
|Shea et al. 2019 ||Health ABC. n = 1323 (635 men) for plasma phylloquinone HPLC measurement, n = 716 for uncarboxylated MGP measurement. Age 74.2 ± 2.8 years, 40% black/60% white.|
Mobility limitation defined as 2 consecutive semiannual reports of difficulties either walking 1/4 miles or climbing 10 steps.
Mobility disability defined as 2 consecutive semiannual reports of huge difficulties/inability to walk 1/4 miles.
Median follow-up: 6.4 (8.6) years for limitation and 10.3 (5.8) years for disability.
|Subjects with circulating vitamin K level <0.5 nmol/L were more likely to develop mobility limitation (OR: 1.27 (96% CI 1.05–1.53)) and disability (OR: 1.34 (96% CI 1.01–1.76)) compared to those with 1.0 nmol/L. |
After adjustment for knee pain, the association with disability was attenuated significantly (OR: 1.26 (96% CI 0.96–1.67)).
Plasma uncarboxylated MGP was not associated with mobility limitation but was associated with incident mobility disability non-linearly (n-shape).
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