Abstract
Objective
Vitamins K and D are important for the function of vitamin K-dependent proteins in joint tissues. It is unclear if these nutrients are mutually important to functional outcomes related to knee osteoarthritis (OA). We evaluated the association of vitamin K and D sufficiency with lower-extremity function in the Health, Aging Body Composition Knee OA Sub-study (Health ABC) and conducted a replication analysis in an independent cohort, the Osteoarthritis Initiative (OAI).
Methods
In Health ABC (60% female, 75±3 years) baseline nutrient status was measured using circulating vitamin K and 25(OH)D. Lower-extremity function was assessed using the short physical performance battery (SPPB) and usual 20-meter gait speed. In the OAI (58% female, 61±9 years), baseline nutrient intake was estimated by food frequency questionnaire. Lower-extremity function was assessed using usual 20-meter gait speed and chair stand completion time. Multivariate mixed models were used to evaluate the association of vitamin K and D status and intake with lower-extremity function over 4–5 years.
Results
Health ABC participants with sufficient plasma vitamin K (≥1.0 nmol/L) and serum 25(OH)D (≥50 nmol/L) generally had better SPPB scores and faster usual gait speed over follow-up (p≤0.002). In the OAI, sufficient vitamin K and vitamin D intake combined was associated with overall faster usual gait speed and chair stand completion time over follow-up (p≤0.029).
Conclusion
Sufficient vitamin K status combined with sufficient vitamin D status was associated with better lower-extremity function in two knee OA cohorts. These findings merit confirmation in vitamin K and D co-supplementation trials.
Osteoarthritis (OA) is the leading cause of lower-extremity disability in older adults (1). Persons with OA frequently have difficulty walking, getting out of a chair, and completing other tasks needed to live independently (2;3). Over 30 million adults in the US are afflicted with OA (4). This estimate is projected to more than double by 2030 (5). The functional limitations and disability related to OA will escalate as well. Identifying novel and modifiable risk factors for impaired lower extremity function is important to develop interventions to reduce functional limitation caused by OA.
Vitamin K and vitamin D status are potential modifiable risk factors for OA-related functional decline. Several clinical trials have tested the effect of vitamin D supplementation on knee OA and overall the results did not support a role for vitamin D supplementation by itself in improving knee OA symptoms or structural outcomes (6–9). Higher vitamin K status has been associated with less knee OA progression and better lower-extremity function observationally (10–12), but vitamin K supplementation has not been tested in knee OA clinical trials. Nutrients don’t occur in the diet alone and don’t function alone. It is biologically plausible for vitamin K and vitamin D to function synergistically in knee OA because the active form of vitamin D (1,25-dihydroxyvitamin D; 1,25(OH)2D) upregulates the expression (via the vitamin D receptor) of several vitamin K-dependent proteins found in joint tissues. This means vitamin D is required for protein synthesis and vitamin K is required for protein function (13–15). The null findings of vitamin D supplementation trials could be explained, in part, by lack of consideration for vitamin K. Currently it is not known if vitamin K and vitamin D status are mutually beneficial to lower-extremity function related to knee OA.
To address this gap, we evaluated the association of vitamin K status combined with vitamin D status and lower extremity function in the Health Aging and Body Composition Study (Health ABC) Knee OA sub-study. Lower circulating phylloquinone (vitamin K1) and 25-hydroxyvitamin D (25(OH)D) concentrations were independently associated with worse lower extremity function in previous separate analyses of Health ABC (16;17). To reduce likelihood that our findings were due to chance, we conducted a replication analysis by evaluating the association of vitamin K intake combined with vitamin D intake with lower extremity function in an independent cohort, the Osteoarthritis Initiative (OAI).
We hypothesized participants with sufficient vitamin K status/intake combined with sufficient vitamin D status/intake would have better lower-extremity function than participants with insufficient status or intakes of either or both nutrients.
METHODS
Primary cohort: the Health, Aging and Body Composition Study Knee Osteoarthritis Sub-study
Between 1997–1998, 3075 70–79-year-old men and women who were free of disabilities in activities of daily living and reported being able to walk ¼ mile and up 10 stairs without stopping were enrolled in Health ABC in Memphis, TN and Pittsburgh, PA. The Knee OA Sub-study, which began in year 2 (1998–1999), included 836 participants with qualifying knee pain and 297 randomly selected controls without knee pain (n=1133). Qualifying knee pain was defined as “knee pain, aching or stiffness on most days for at least one month” (12). We excluded 8 participants who were missing circulating phylloquinone or 25(OH)D measures and 56 who reported taking warfarin (Coumadin), which is a vitamin K antagonist at baseline or during follow-up, leaving 1069 available for analysis. Excluded participants did not significantly differ from those included in any pertinent characteristics (all between group difference p>0.07). One participant was excluded from our 400-meter walk analysis because their recorded completion time (52.4 seconds) was more than 4 standard deviations from the mean.
Vitamin K and vitamin D status
Plasma phylloquinone (the predominate circulating form of vitamin K) and serum 25(OH)D were measured from archived samples obtained at the year 2 clinic-visit (1998–1999) using reverse-phase HPLC and radioimmunoassay, respectively, as described (12;16;17). Sufficient plasma phylloquinone was defined as ≥1.0 nmol/L, the concentration achieved when Institute of Medicine’s (IOM) recommended dietary intakes are met (18;19) and sufficient serum 25(OH)D was defined according to the IOM as ≥50 mmol/L (20). Participants were categorized as follows: (1) insufficient plasma phylloquinone (<1.0 nmol/L) and insufficient serum 25(OH)D (<50 nmol/L); (2) insufficient plasma phylloquinone (<1.0 nmol/L) and sufficient serum 25(OH)D (≥50 mmol/L); (3) sufficient plasma phylloquinone (≥ 1.0 nmol/L) and insufficient serum 25(OH)D (<50 nmol/L); (4) sufficient plasma phylloquinone (≥ 1.0 nmol/L) and sufficient serum 25(OH)D (≥50 mmol/L).
Lower-extremity function
In year 1 (baseline), 4, and 6 lower-extremity function was assessed using the Short Physical Performance Battery (SPPB), which consisted of the following tasks: standing balance (side-by-side, semi-tandem, full-tandem for 10 seconds), time to complete 5 chair stands, and 6-meter walk (to calculate gait speed). Each task was scored on a 0–4 scale and the scores were summed for an overall range of 0–12 (21). The Health ABC Physical Performance Battery (Health ABC -PPB, score range 0–4) was also administered to minimize potential ceiling effects as described (16). Higher scores indicated better performance. The usual 20-meter gait speed and 400-meter walk time were assessed in years 2, 4, and 6 using a 20-meter course marked with cones at each end (16), with the year 2 measure being considered baseline. Exclusion criteria for lower-extremity function tests are described in detail elsewhere (16).
Additional covariates
At the baseline clinic visit demographic and lifestyle characteristics, including age, sex, race, education and smoking status were ascertained using interviewer-administered questionnaires. Triglycerides were measured in fasting serum on a commercially-available analyzer (Vitros 950; Johnson & Johnson, Rochester, NY). Depressive symptoms were assessed using the 10-item Center for Epidemiologic Studies Depression Scale (CESD10) (22). At the year 2 clinic visit, weight and height were measured and BMI was calculated as weight (kg)/(height (m)2). Physical activity was based on the reported time spent in walking for exercise or in other walking (e.g., for transportation) over the previous week (16). The Healthy Eating Index (HEI) score was calculated using dietary intake data obtained from an interviewer-administered 108-item Food Frequency Questionnaire (FFQ) developed specifically for Health ABC, as described (23;24). Statin use was recorded and coded using the Iowa Drug Information system. The season during which the blood sample was obtained was included to account for seasonal effects.
Replication cohort: the Osteoarthritis Initiative
The OAI is an observational study focused on knee OA development and progression that began in 2004 when 4796 participants between 45–79 years old were enrolled from sites in Baltimore, MD, Columbus, OH, Pittsburgh, PA, and Pawtucket, RI. The OAI study protocol (25) was approved by the institutional review board of the all clinical sites and the OAI Coordinating Center, University of California San Francisco. All participants provided written informed consent. We included participants in the incidence cohort and progression cohort. We excluded participants who did not complete a FFQ at the baseline visit (n=129) or whose reported caloric intake was < 500 kcal/day or > 5000 kcal/day, whose FFQ was incomplete (defined as ≥15% missing data), or for whom vitamin K and vitamin D intakes were not available (n=153). Ten participants who did not have either a 20-meter walk time or chair stand completion time at baseline and 29 participants who reported taking warfarin were also not included in our baseline sample. This left 4475 OAI participants available for inclusion. Compared to included participants, those excluded were on average 2 years younger (p<0.001), had, on average, a 1 kg/m2 higher BMI (p<0.001), were more likely to be African-American (p<0.001) and less likely to have graduated high school (p<0.001).
Vitamin K and Vitamin D Dietary Intake
Usual dietary intakes were assessed using the semi-quantitative Block Brief 2000 Food Frequency Questionnaire (FFQ) (26). For each of the 70 food items listed, a commonly used portion size/unit was specified and participants were asked how often over the previous year they consumed that food (never, a few times per year, once a month, 2–3 times per month, once a week, twice a week, 3–4 times per week, 5–6 times per week, or daily). Daily intakes of vitamin K (phylloquinone, the primary dietary form of vitamin K in US diets) and vitamin D (vitamin D2 + vitamin D3) were calculated by multiplying the frequency of consumption of each food by the vitamin K/vitamin D/nutrient content (obtained from the US Department of Agriculture food composition database by NutritionQuest) then adding the vitamin content of all reported foods (27). This FFQ was validated in middle-aged women against three four-day food records and in older men against two seven-day food records. (27)
Sufficient vitamin K intake was defined according to IOM recommendations as ≥ 90 μg/day for women and ≥ 120 μg/day for men (19). Sufficient vitamin D intake was defined according to IOM recommendations as ≥ 600 IU/day for men and women <70 years old and ≥ 800 IU/day for men and women ≥70 years old (20). Vitamin D intake included vitamin D from food and supplements while vitamin K intake included food sources only. Vitamin K is generally not consumed in appreciable amounts from supplements in the US (28), so vitamin K from supplements was not ascertained in the OAI. Participants were categorized as follows: (1) insufficient vitamin K intake and insufficient vitamin D intake; (2) insufficient vitamin K intake and sufficient vitamin D intake; (3) sufficient vitamin K intake and insufficient vitamin D intake; (4) sufficient vitamin K intake and sufficient vitamin D intake.
Lower-extremity function
At the baseline and at the 12-, 24-, 36- and 48-month clinic visits, participants were asked to complete two trials of rising from a chair and sitting down 5 times. The average time was used as ‘chair stand time’. If one trial was missing, the other trial’s time was used. Gait speed over 20-meters was assessed using a timed walk test. Participants were instructed to walk at their usual pace between 2 cones placed 20 meters apart. The average time of two trials was used to calculate gait speed (m/s). If one trial was missing, the other trial’s time was used. At the baseline, 24- and 48-month clinic visits, participants walked the 20-meter course 20 times to determine the time to walk 400 meters (29). Only one 400-meter trial was performed. Participants could take as many breaks as needed within a 15-minute time limit. The participants wore their usual footwear and used walking aids/devices as needed.
Additional covariates
Demographic characteristics and smoking status were self-reported at the baseline clinic visit. Physical activity was evaluated using the Physical Activity Scale for the Elderly (PASE) (30). BMI was calculated from weight and height measured annually using a calibrated medical scale. Depressive symptoms were evaluated using the CES-D and depression was defined as a CESD>16 on the 20-item questionnaire (22). Energy intake (kcal/day) was derived from the FFQ and HEI score was calculated from the FFQ to account for potential confounding by healthy diet (24).
Statistical Approach
In each cohort, participant characteristics at baseline were compared across categories using chi-square or analysis of variance. Skewed variables were normalized using the natural log.
In Health ABC, the association of phylloquinone-25(OH)D sufficiency with change in Health ABC-PPB, SPPB, 20-meter gait speed, and 400-meter walk time over 4–5 years of follow-up was evaluated using linear mixed models. Covariates in adjusted models were chosen based on our previous analyses and biological plausibility (16;17). They included age, sex, race, site, smoking status, energy intake, HEI score, time spent walking per week (for physical activity), triglycerides and statin use (because plasma phylloquinone is transported by triglyceride-rich lipoproteins), season of blood draw (to account for seasonal differences in serum 25(OH)D), highest level of education (all baseline), depression, and time-varying BMI. Product terms (phylloquinone-25(OH)D sufficiency category*follow-up year) were included to evaluate if the association changed over time. Within-year trend tests were performed by entering phylloquinone-25(OH)D sufficiency category as an ordinal exposure. We also evaluated whether circulating phylloquinone-25(OH)D sufficiency was associated with the ability to complete the 400-meter walk at baseline and during follow-up using logistic regression. We tested for effect modification by sex and race using product terms (ie. circulating phylloquinone-25(OH)D category*race), but none was detected (all interaction p≥0.466) so all participants were analyzed together.
In the OAI, linear mixed models were used to evaluate the association of sufficient vitamin K and vitamin D intake with chair stand time, usual 20-meter gait speed, and 400-meter walk time over 4 years of follow-up. Covariates in adjusted models were chosen to be consistent with our Health ABC analyses and to adjust for overall dietary intakes. They included age, sex, race, highest level of education, smoking, energy intake, HEI score, PASE score (for physical activity) (all baseline), depression, and BMI (time-varying). A product term (category*follow-up year) was included, within-year trend tests were performed by entering nutrient intake category as an ordinal exposure. Chair stand time and gait speed were natural log-transformed to reduce skewness so results are reported as unadjusted and adjusted geometric means with SEMs calculated using the delta method (SEM=(geometric mean)x(SEM of ln-transformed outcome)). The association between vitamin K-vitamin D intake and ability to complete the 400-meter walk at baseline and during follow-up was evaluated using logistic regression.
All analyses were carried out using SAS v 9.3 (Cary, NC). Statistical significance was set at p<0.05 (two-sided). If within-year trend tests were significant (p<0.05), the vitamin K-vitamin D sufficient group was compared to the other three groups in post hoc analyses using a Bonferroni–adjusted p-value <0.0167 (0.05/3 comparisons).
RESULTS
Health ABC Knee OA Sub-study
Participant characteristics according to circulating phylloquinone-25(OH)D status categories are shown in Table 1. Briefly, participants with sufficient phylloquinone combined with sufficient 25(OH)D were more likely to be male and/or white. As expected, circulating phylloquinone-25(OH)D status varied with season and serum triglycerides. Participants with sufficient circulating phylloquinone combined with sufficient 25(OH)D at baseline had overall better HABC-PPB and SPPB scores and faster 20-meter gait speed over 4–5 years (Figure 1, Table 2). Circulating phylloquinone-25(OH)D status was not significantly associated with 400-meter walk completion time among those who completed the walk (Table 2) or with ability to complete the 400-meter walk at baseline or during follow-up. (Data not shown.) Except for SPPB (category*year interaction p=0.001), the change in lower-extremity function over time did not differ according to circulating phylloquinone-25(OH)D status.
Table 1.
Health ABC Knee OA study participant characteristics according to circulating phylloquinone and 25(OH)D categories. Data are means ± SD, unless otherwise indicated.
| plasma phylloquinone <1.0 nmol/L & serum 25(OH)D <50 nmol/L (n=257) |
plasma phylloquinone <1.0 nmol/L & serum 25(OH)D ≥50 nmol/L (n=459) |
plasma phylloquinone ≥1.0 nmol/L & serum 25(OH)D <50 nmol/L (n=120) |
plasma phylloquinone ≥1.0 nmol/L & serum 25(OH)D ≥50 nmol/L (n=233) |
p-value b | |
|---|---|---|---|---|---|
| Age, yr | 75±3 | 75±3 | 74±3 | 74±3 | 0.114 |
| Female (n(%)) | 172 (67) | 247 (54) | 87 (73) | 134 (58) | <0.001 |
| Race | <0.001 | ||||
| White (n(%)) | 72 (28) | 311 (68) | 35 (29) | 150 (64) | |
| Black (n(%)) | 185 (72) | 148 (32) | 85 (71) | 83 (36) | |
| BMI, kg/m2 | 28.8±5.6 | 27.0±4.5 | 30.7±5.6 | 27.4±4.3 | <0.001 |
| Triglycerides, mg/dl c | 108±52 | 118±66 | 130±109 | 135±92 | <0.001 |
| Statin use (n(%)) | 36 (14) | 65 (14) | 15 (13) | 39 (17) | 0.689 |
| Healthy Eating Index score | 66±12 | 70±11 | 68±12 | 71±12 | <0.001 |
| Time spent walking per week (n(%)) | <0.001 | ||||
| ≥ 150 min | 38 (15) | 142 (31) | 21 (18) | 70 (30) | |
| 1–149 min | 81 (32) | 139 (30) | 37 (31) | 76 (33) | |
| 0 min | 138 (54) | 177 (39) | 62 (52) | 87 (19) | |
| Season of blood draw (n(%)) | |||||
| December–February | 71 (28) | 108 (24) | 39 (33) | 43 (18) | <0.001 |
| March–May | 77 (30) | 114 (25) | 38 (32) | 74 (32) | |
| June–August | 33 (13) | 91 (20) | 15 (13) | 65 (28) | |
| September–November | 76 (30) | 146 (32) | 28 (23) | 51 (22) | |
| Smoker, current or former n(%)) | 145 (56) | 245 (53) | 62 (52) | 104 (45) | 0.075 |
| Education (n(%)) | |||||
| < High school | 92 (36) | 103 (23) | 41 (34) | 56 (24) | <0.001 |
| High school graduate | 88 (34) | 153 (33) | 37 (31) | 74 (32) | |
| ≥ College graduate | 76 (30) | 201 (44) | 41 (34) | 103 (44) | |
| Depression (n(%)) | 14 (5) | 34 (7) | 7 (6) | 12 (5) | 0.618 |
| Clinic site (n(%)) | |||||
| Pittsburgh | 154 (60) | 253 (55) | 49 (41) | 102 (44) | <0.001 |
Figure 1. Lower extremity function according to plasma phylloquinone and serum 25(OH)D sufficiency a over 4–5 years in the Health ABC Knee OA sub-study. Data are LS arithmetic means with SEM, adjusted for age, sex, race, study site, triglycerides, statin use, season, Healthy Eating Index score, walk time per week, smoking status, highest education level (all baseline), BMI (time-varying).
aSufficient plasma phylloquinone defined as ≥ 1.0 nmol/L. Adequate serum 25(OH)D defined as ≥ 50 mmol/L (18–20).
Table 2.
Lower-extremity function across circulating phylloquinone and 25(OH)D status categories in the Health ABC Knee OA study a
| n | insufficient plasma phylloquinone & insufficient serum 25(OH)D (n=257) |
insufficient plasma phylloquinone & sufficient serum 25(OH)D (n=459) |
sufficient plasma phylloquinone & insufficient serum 25(OH)D (n=120) |
sufficient plasma phylloquinone & sufficient serum 25(OH)D (n=233) |
p-values for circulating phylloquinone-25(OH)D category b | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| within year trend | overall trend | year interaction | |||||||||||
|
HEALTH ABC PPB (0–4)
| |||||||||||||
| unadjusted | year 1 | 1022 | 1.99±0.04 e | 2.18±0.03 | 2.02±0.05 e | 2.28±0.04 | <0.001 | <0.001 | 0.786 | ||||
| year 4 | 918 | 1.80±0.04 e | 1.98±0.04 | 1.80±0.06 e | 2.07±0.04 | <0.001 | |||||||
| year 6 | 806 | 1.57±0.04 e | 1.79±0.03 | 1.60±0.06 e | 1.93±0.04 | <0.001 | |||||||
| adjusted c | year 1 | 955 | 2.05±0.04 e | 2.12±0.03 e | 2.11±0.05 | 2.22±0.04 | <0.001 | <0.001 | 0.930 | ||||
| year 4 | 864 | 1.87±0.04 | 1.93±0.03 | 1.91±0.05 | 2.02±0.04 | 0.026 | |||||||
| year 6 | 756 | 1.67±0.04 e | 1.75±0.03 e | 1.70±0.06 | 1.88±0.05 | 0.003 | |||||||
|
SPPB (0–12) | |||||||||||||
| unadjusted | year 1 | 1049 | 9.63±0.10 e | 9.95±0.07 e | 9.76±0.14 e | 10.24±0.10 | <0.001 | 0.001 | |||||
| year 4 | 935 | 9.12±0.15 e | 9.40±0.11 | 8.95±0.21 e | 9.76±0.15 | 0.003 | |||||||
| year 6 | 840 | 8.16±0.18 e | 8.90±0.13 e | 8.37±0.25 e | 9.51±0.19 | <0.001 | |||||||
| adjusted c | year 1 | 980 | 9.58±0.16 e | 9.56±0.13 e | 9.81±0.21 | 9.88±0.16 | 0.017 | 0.001 | |||||
| year 4 | 877 | 9.08±0.17 | 9.06±0.13 | 9.05±0.22 | 9.39±0.16 | 0.181 | |||||||
| year 6 | 785 | 8.16±0.15 e | 8.485±0.11e | 8.34±0.21 | 9.11±0.14 | 0.003 | |||||||
|
Usual 20-m gait speed, m/sec | |||||||||||||
| unadjusted | year 2 | 1041 | 1.05±0.01 e | 1.13±0.01 | 1.05±0.01 e | 1.16±0.01 | <0.001 | <0.001 | 0.899 | ||||
| year 4 | 902 | 1.04±0.01 e | 1.12±0.01 | 1.05±0.02 e | 1.16±0.01 | <0.001 | |||||||
| year 6 | 798 | 9.98±0.02 e | 1.06±0.01 e | 1.00±0.03 e | 1.11±0.02 | <0.001 | |||||||
| adjusted c | year 2 | 980 | 1.08±0.02 | 1.10±0.01 | 1.10±0.02 | 1.12±0.01 | 0.044 | 0.002 | 0.549 | ||||
| year 4 | 854 | 1.08±0.01 e | 1.09±0.01 e | 1.10±0.02 | 1.13±0.01 | 0.001 | |||||||
| year 6 | 748 | 1.02±0.01 e | 1.03±0.01 e | 1.05±0.02 | 1.09±0.01 | 0.003 | |||||||
|
400-m walk completion time (sec) d | |||||||||||||
| unadjusted | year 2 | 696 | 349±5 e | 323±3 | 348±8 e | 324±6 | <0.001 | <0.001 | 0.283 | ||||
| year 4 | 590 | 360±5 e | 334±3 | 364±8 e | 331±5 | <0.001 | |||||||
| year 6 | 507 | 392±6 e | 359±4 | 393±8 e | 351±5 | <0.001 | |||||||
| adjusted c | year 2 | 661 | 335±5 | 328±4 | 333±7 | 327±5 | 0.053 | 0.068 | 0.277 | ||||
| year 4 | 562 | 344±5 | 337±4 | 346±7 | 333±5 | 0.053 | |||||||
| year 6 | 478 | 374±7 | 361±5 | 374±9 | 350±6 | 0.016 | |||||||
Sufficient plasma phylloquinone defined as ≥ 1.0 nmol/L. Sufficient serum 25(OH)D defined as ≥ 50 mmol/L (18–20).
To calculate trend p-values, the insufficient circulating phylloquinone & sufficient 25(OH)D category and the insufficient circulating phylloquinone & sufficient 25(OH)D category were treated as one group. It is premature to treat rank these two groups with respect to each other by assigning ordinal values because the relative importance of one vitamin over the other in knee OA-related lower extremity function is unclear.
Covariates: age, sex, race, site, triglycerides, statin use, highest level of education, season of blood draw, Healthy Eating Index score, time spent walking per week, smoking (current or former vs never), depression, (all baseline) and BMI (time-varying)
Excluded participants unable to complete the 400 m walk (35% at year 2, 19% additionally at year 4, 16% additionally at year 6)
Different from sufficient circulating phylloquinone & sufficient 25(OH)D category at p<0.0167, when within year p<0.05.
OAI
Participant characteristics according to baseline vitamin K-vitamin D intake categories are provided in Table 3. Those reporting sufficient intakes of both nutrients were more likely to be female and/or Caucasian. The change in 20-meter gait speed and chair stand completion time over follow-up differed according to vitamin K-vitamin D intake (category*year interaction p<0.001 and p=0.003 respectively), but the change in 400-meter walk time did not (category*year interaction p=0.459). Overall, sufficient intake of vitamin K combined with sufficient intake of vitamin D at baseline was associated with overall faster 20-meter gait speed, chair stand completion time, and 400-meter walk time (among those able to complete the walk) (Figure 2, Table 4). The combination of vitamin K and vitamin D intake was not significantly associated with ability to complete the 400-meter walk at baseline or over follow-up. (Data not shown.)
Table 3.
Osteoarthritis Initiative participant characteristics according to sufficient vitamin K intake and sufficient vitamin D, intake categories a. Data are means ± SD, unless otherwise indicated
| insufficient vitamin K intake and insufficient vitamin D intake (n=1351) |
insufficient vitamin K intake and sufficient vitamin D intake (n=236) |
sufficient vitamin K intake and insufficient vitamin D intake (n=2259) |
sufficient vitamin K intake and sufficient vitamin D intake (n=629) |
p-value b | |
|---|---|---|---|---|---|
| Age, yr | 61±10 | 61±7 | 62±9 | 61±8 | 0.039 |
| Female (n(%)) | 543 (40) | 122 (52) | 1446 (64) | 503 (80) | <0.001 |
| Race Caucasian (n(%)) | 1104 (82) | 214 (91) | 1699 (75) | 551 (88) | <0.001 |
| African-American (n(%)) | 213 (16) | 12 (5) | 496 (22) | 67 (11) | |
| BMI, kg/m2 | 28.7±4.6 | 28.1±4.3 | 29.0±4.9 | 27.9±4.9 | <0.001 |
| Energy, kcal/d | 1259±501 | 1276±474 | 1484±591 | 1547±586 | <0.001 |
| Healthy Eating Index score | 54±9 | 57±9 | 62±9 | 66±8 | <0.001 |
| Physical activity (PASE) score | 159±83 | 160±83 | 160±82 | 167±81 | 0.261 |
| Smoker, current or former (n(%)) | 602 (45) | 98 (42) | 1131 (50) | 275 (44) | <0.001 |
| Education (n(%)) | |||||
| < High school | 51 (4) | 4 (2) | 86 (4) | 10 (2) | 0.014 |
| High school graduate | 514 (38) | 77 (33) | 855 (38) | 223 (35) | |
| ≥ College graduate | 786 (58) | 155 (65) | 1314 (58) | 396 (63) | |
| Depression (n(%)) | 146 (11) | 21 (9) | 236 (11) | 38 (6) | 0.004 |
Sufficient vitamin K intake defined as ≥ 90 μg/day for women and ≥ 120 μg/day for men. Sufficient vitamin D intake defined as ≥ 600 IU for men and women < 70 years old and ≥ 800 IU for men and women ≥ 71 years old (included food and supplements). (19;20)
based on ANOVA (continuous outcomes) or Chi square test (categorical outcomes), unless otherwise indicated
Figure 2. Lower extremity function according to vitamin K intake and vitamin D intake a categories over 4 years in the Osteoarthritis Initiative. Data are LS geometric mean with SEM, adjusted for age, sex, race, study site, Healthy Eating Index score, PASE score, smoking status, highest education level (all baseline), BMI (time-varying).
aSufficient vitamin K intake defined as ≥ 90 μg/day for women and ≥ 120 μg/day for men. Sufficient vitamin D intake defined as ≥ 600 IU for men and women < 70 years old and ≥ 800 IU for men and women ≥ 71 years old (included food and supplements). (19;20).
Table 4.
Lower extremity function according to adequate vitamin K and vitamin D intake categories a over 4 years in the Osteoarthritis Initiative
| n | insufficient vitamin K intake and insufficient vitamin D intake (n=1351) | insufficient vitamin K intake and sufficient vitamin D intake (n=236) | sufficient vitamin K intake and insufficient vitamin D intake (n=2259) | sufficient vitamin K intake and sufficient vitamin D intake (n=629) | p-values for vitamin K - vitamin D intake category b | ||||
|---|---|---|---|---|---|---|---|---|---|
| within year trend | overall trend | year interaction | |||||||
|
Usual 20-m gait speed, m/sec
c
| |||||||||
| unadjusted | baseline | 4469 | 1.29±0.01 e | 1.31±0.01 | 1.29±0.01 e | 1.35±0.01 | <0.001 | <0.001 | |
| 12 month | 3986 | 1.30±0.01 e | 1.35±0.01 | 1.29±0.01 e | 1.36±0.01 | <0.001 | |||
| 24 month | 3731 | 1.28±0.01 e | 1.33±0.01 | 1.28±0.01 e | 1.34±0.01 | <0.001 | |||
| 36 month | 3638 | 1.28±0.01 e | 1.33±0.01 | 1.28±0.01 e | 1.34±0.01 | 0.002 | |||
| 48 month | 3472 | 1.27±0.01 e | 1.31±0.01 | 1.25±0.01 e | 1.32±0.01 | 0.030 | |||
| adjusted d | baseline | 4328 | 1.19±0.01 e | 1.19±0.01 | 1.21±0.01 e | 1.23±0.01 | <0.001 | 0.001 | |
| 12 month | 3822 | 1.20±0.01 e | 1.22±0.01 e | 1.22±0.01 e | 1.25±0.01 | <0.001 | |||
| 24 month | 3590 | 1.19±0.01 e | 1.20±0.01 | 1.20±0.01 e | 1.23±0.01 | <0.001 | |||
| 36 month | 3510 | 1.18±0.01 e | 1.20±0.01 | 1.20±0.01 e | 1.23±0.01 | <0.001 | |||
| 48 month | 3354 | 1.18±0.01 e | 1.19±0.01 | 1.18±0.01e | 1.22±0.01 | 0.003 | |||
|
Chair stands time, sec c | |||||||||
| unadjusted | baseline | 4251 | 10.98±0.09 e | 10.66±0.18 | 11.25±0.07 e | 10.60±0.11 | 0.159 | <0.001 | 0.951 |
| 12 month | 3728 | 10.70±0.09 e | 10.19±0.18 | 10.84±0.07 e | 10.15±0.11 | 0.008 | |||
| 24 month | 3546 | 10.52±0.10 e | 9.82±0.18 | 10.67±0.07 e | 10.03±0.12 | 0.015 | |||
| 36 month | 3369 | 10.53±0.10 e | 10.10±0.18 | 10.69±0.08 e | 10.05±0.12 | 0.029 | |||
| 48 month | 3306 | 10.36±0.10 e | 9.95±0.19 | 10.50±0.08 e | 9.63±0.12 | <0.001 | |||
| adjusted d | baseline | 4119 | 12.02±0.19 | 11.97±0.26 | 11.99±0.17 | 11.71±0.15 | 0.098 | 0.003 | |
| 12 month | 3572 | 11.90±0.18 e | 11.51±0.25 | 11.73±0.17 e | 11.32±0.15 | 0.002 | |||
| 24 month | 3409 | 11.72±0.18 e | 11.31±0.25 | 11.60±0.17 e | 11.21±0.15 | 0.002 | |||
| 36 month | 3254 | 11.76±0.18 e | 11.54±0.26 | 11.62±0.17 e | 11.23±0.15 | <0.001 | |||
| 48 month | 3190 | 11.55±0.18 e | 11.37±0.26 | 11.42±0.21 e | 10.76±0.14 | <0.001 | |||
|
400-meter walk completion time, sec | |||||||||
| unadjusted | baseline | 4312 | 309±2 e | 304±3 | 312±1 e | 300±2 | 0.012 | <0.001 | 0.554 |
| 24 month | 3393 | 315±2 e | 306±3 | 317±1 e | 306±2 | 0.023 | |||
| 48 month | 3041 | 318±2 | 308±4 | 322±1 e | 309±2 | 0.137 | |||
| adjusted d | baseline | 4179 | 332±3 e | 330±4 | 327±3 | 322±3 | 0.001 | <0.001 | 0.459 |
| 24 month | 3270 | 338±3 e | 334±4 | 332±3 e | 327±3 | <0.001 | |||
| 48 month | 2940 | 341±3 e | 335±4 | 337±3 e | 330±3 | <0.001 | |||
Sufficient vitamin K intake defined as ≥ 90 μg/day for women and ≥ 120 μg/day for men. Sufficient vitamin D intake defined as ≥ 600 IU for men and women < 70 years old and ≥ 800 IU for men and women ≥ 71 years old (included food and supplements (19;20).
To calculate trend p-values the insufficient vitamin K intake-sufficient vitamin D intake category and the sufficient vitamin K intake-insufficient vitamin D intake category were treated as one group. It is premature to treat rank these two groups with respect to each other because the relative importance of one vitamin over the other in knee OA-related lower extremity function is unclear.
Data are geometric means ± SEM
Adjusted for age, sex, race, site, energy intake (kcal/day), smoking, PASE score, Healthy Eating Index score, highest level of education (all baseline), depression, BMI (time varying, annually)
Different from adequate vitamin K and vitamin D intake group p<0.0167, when within year p<0.05.
DISCUSSION
Vitamin K and vitamin D are essential nutrients that have been implicated in OA and its related effects on lower-extremity function. A role for these two nutrients is mechanistically linked because the expression of the vitamin K-dependent proteins in joint tissues requires the active form of vitamin D (13–15). In the Health ABC Knee OA sub-study, sufficient circulating phylloquinone (≥ 1.0 nmol/L) combined with sufficient 25(OH)D (≥ 50 nmol/L) was associated with generally better physical performance battery scores and faster 20-meter gait speed at baseline and over follow-up compared to sufficient concentrations of either nutrient alone or insufficient concentrations of both. These findings were replicated in the OAI, a cohort comprised of adults with or at higher risk for radiographic knee OA (25). OAI participants who reported consuming the IOM recommended intakes of both vitamins K and D at baseline had faster 20-meter gait speed and chair stand completion time longitudinally than those who reported insufficient intakes of either or both nutrients.
While low vitamin K status has been associated with a higher prevalence of radiographic knee OA and with more knee OA development and progression (10–12;31), evidence of vitamin K’s role in lower-extremity function related to knee OA is relatively limited. We previously reported, in the Health ABC knee OA sub-study those with plasma phylloquinone <1.0 nmol/L had generally lower physical performance battery scores and slower 20-meter gait speed over 4–5 years of follow-up (17). Vitamin D status has been well-studied in relation to knee OA and related lower-extremity function and pain observationally, with conflicting results (32;33). Three of the four randomized placebo-controlled trials of OA patients did not find any consistent benefit of vitamin D supplementation by itself on knee pain or structural knee OA progression (6–9), indicating vitamin D supplementation alone is not likely to reduce OA progression or improve the functional consequences of knee OA. Compared to healthy individuals, knee OA patients have worse lower-extremity function, including slower gait speed (34;35). Therefore, our current findings suggest vitamin K repletion combined with vitamin D repletion could benefit lower-extremity function related to knee OA. However, this needs to be verified in randomized clinical trials.
The effect of higher vitamin K status combined with higher vitamin D status on lower-extremity function appears to be additive. For example, in Health ABC those with circulating phylloquinone ≥1.0 nmol/L combined with 25(OH)D ≥50 nmol/L had, on average, a 0.04–0.07 m/s faster 20-meter gait speed (adjusted for confounders) than participants with phylloquinone <1.0 nmol/L or with 25(OH)D <50 nmol/L. When these nutrients were analyzed separately, the difference in 20-meter gait speed between participants with < or ≥ 1.0 nmol/L plasma phylloquinone was 0.02–0.03 m/s (17) and the difference between participants with < or ≥ 50 nmol/L serum 25(OH)D was also, on average, 0.02–0.03 m/s (16). A 0.05 m/s difference in 20-meter gait speed is considered clinically meaningful (36).
Vitamin K has an established biological function as an enzymatic co-factor in the γ-carboxylation of certain calcium binding proteins (commonly known as vitamin K-dependent proteins), including matrix gla protein (MGP). When MGP is carboxylated, which requires vitamin K, it inhibits soft-tissue calcification (37;38). Uncarboxylated MGP (ucMGP, which is non-functional) is abundant in human arthritic articular cartilage, while the carboxylated form (cMGP, which is functional) is more abundant in healthy articular cartilage (39). Calcium crystal deposition and articular cartilage and meniscal calcification (chondrocalcinosis) contribute to OA (40) and chondrocalcinosis has been associated with more lower-extremity disability in older adults (41). The transcription of MGP and other vitamin K-dependent proteins implicated in OA is upregulated by 1,25(OH)2D (13–15). Moreover, in animal models 1,25(OH)2D promoted soft-tissue calcification which corresponded to an increase in ucMGP (37;42). When vitamin K is available to carboxylate the newly synthesized ucMGP, calcium deposition is reduced (43). Other vitamin K-dependent proteins including Gas6, Gla-rich protein, and osteocalcin are found in joint tissues that could contribute to the beneficial effects of vitamin K, although their function in the joint is not well-understood (44–46). Future studies are needed to determine whether the null findings of vitamin D supplementation trials are explained in part by lack of consideration for vitamin K.
The longitudinal design and inclusion of two separate knee OA cohorts are notable strengths to our study. Nutritional biomarkers, such as circulating phylloquinone and 25(OH)D used in Health ABC, are considered more robust indicators of nutritional status compared to self-reported dietary intakes (47). However, circulating phylloquinone and 25(OH)D were measured at one time point, so neither necessarily reflects long-term nutritional status. Repeated measures would provide a better indication of nutrient status over time, but were not available. Assessing nutrient status using self-reported diet questionnaires, such as the FFQ, carries inherent limitations (48). However, the FFQ queries intakes over the previous year, providing estimates of long-term intakes. That our findings in Health ABC (using biomarkers) are consistent with our findings in the OAI (using FFQ-estimated intakes) strengthens the overall results. While 25(OH)D is the established biomarker of vitamin D status, there is not yet an established clinical measure of vitamin K status. We used plasma phylloquinone because it is considered a global indicator of vitamin K status and reflects dietary intake, which was assessed in the OAI (49). The IOM recommends 25(OH)D concentrations of ≥50 nmol/L as sufficient (20), but there is not yet a clinical recommendation for sufficient circulating phylloquinone. We chose ≥1.0 nmol/L because that is the concentration achieved when the current IOM recommendations (90–120 μg/day for women and men ≥ 18 years) are met. (18;19) It is plausible a higher level is needed to meet all of the physiological needs for vitamin K, but this has not yet been extensively studied. Some have suggested ≥ 75 nmol/L 25(OH)D is needed for vitamin D sufficiency (50). In the full Health ABC cohort, participants with serum 25(OH)D ≥75 nmol/L had significantly faster 400-meter walk pace compared to those with <75 nmol/L (16). We explored using 75 nmol/L 25(OH)D as a cut-point, but there were only 95 participants with circulating phylloquinone ≥ 1.0 nmol/L combined with 25(OH)D ≥75 nmol/L, which limited our ability to detect consistent differences in that group. Sufficient vitamin K and D status reflect healthy lifestyles, which could also be associated with better lower-extremity function in those with or at risk for knee OA. We attempted to address this confounding by adjusting for the HEI score (an indication of the overall health of the diet), physical activity and other healthy lifestyle indicators (ie. smoking). However, residual confounding cannot be discounted. We were also unable to establish causality due to the observational design.
In conclusion, sufficient vitamin K status and intake combined with sufficient vitamin D status and intake appear to be beneficial to lower-extremity function. In most trials in knee OA, vitamin D supplementation alone did not improve structural or functional knee OA outcomes (6–9). To date there have not been any trials designed to test the effect of vitamin K supplementation on knee OA or function. Our findings suggest trials designed to test the effect of vitamin K in combination with vitamin D are warranted.
Significance and Innovation.
This study determined the mutual association of vitamin K and vitamin D status and intake with lower-extremity function in two separate knee OA cohorts.
In two cohorts, participants with sufficient vitamin K status/intake combined with sufficient vitamin D status/intake at baseline had better lower-extremity function over 4–5 years of follow-up.
These findings suggest vitamin K and vitamin D may be mutually beneficial to improve the functional consequences related to knee OA.
Acknowledgments
The OAI is a public-private partnership comprised of five contracts (N01-AR-2-2258; N01-AR-2-2259; N01-AR-2-2260; N01-AR-2-2261; N01-AR-2-2262) funded by the National Institutes of Health, a branch of the Department of Health and Human Services, and conducted by the OAI Study Investigators. Private funding partners include Merck Research Laboratories; Novartis Pharmaceuticals Corporation, GlaxoSmithKline; and Pfizer, Inc. Private sector funding for the OAI is managed by the Foundation for the National Institutes of Health. This study was conducted using publicly-available OAI data and its contents do not necessarily reflect the opinions of OAI Study Investigators, the NIH, or the private funding partners.
Additional support was provided from National Institute of Arthritis and Musculoskeletal and Skin Diseases (K01AR063167 & R21AR062284), The Arthritis Foundation (New Investigator Grant), National Institute on Aging Intramural Research Program and contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106; grant R01-AG028050; the National Institute of Nursing Research (R01-NR012459); Wake Forest Older Americans Independence Center (P30 AG021332), and the USDA ARS Cooperative Agreement 58-1950-7-707. Any opinions, findings, or conclusion expressed in this publication are those of the authors and do not necessarily reflect the view of the US Department of Agriculture
Footnotes
Dr. Shea had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design: Shea, Booth, Loeser, Kritchevsky, McAlindon. Acquisition of data: Shea, Booth, Loeser, Houston, Kritchevsky, McAlindon. Analysis and interpretation of data: Shea, Loeser, McAlindon, Houston, Booth. Drafting and/or revising article for important intellectual content: Shea, Booth, Loeser, Houston, Kritchevsky, McAlindon. All authors approved the final version submitted for publication
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