The Journal of Clinical Endocrinology & Metabolism, 2024, 00, 1–10

https://doi.org/10.1210/clinem/dgae150
Advance access publication 15 March 2024
Clinical Research Article

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Effects of Supplemental Vitamin D3, Omega-3 Fatty Acids
on Physical Performance Measures in the VITamin D and
OmegA-3 TriaL
Sharon H. Chou,1,2 Nancy R. Cook,2,3,4 Gregory Kotler,3 Eunjung Kim,3 Trisha Copeland,3
I-Min Lee,2,3,4 Peggy M. Cawthon,5,6 Julie E. Buring,2,3,4 JoAnn E. Manson,2,3,4
and Meryl S. LeBoff1,2
1
Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA
2
Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
3
Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02215, USA
4
Department of Epidemiology, Harvard T. H. Chan School of Public Health, Harvard University, Boston, MA 02115, USA
5
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA 94158, USA
6
Research Institute, California Pacific Medical Center, San Francisco, CA 94143, USA
Correspondence: Meryl S. LeBoff, MD, Harvard Medical School, Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and
Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA. Email: mleboff@bwh.harvard.edu.

Abstract
Context: Declining muscle strength and performance in older adults are associated with falls, fractures, and premature death.
Objective: This work aimed to determine whether supplementation with vitamin D3 or omega-3 fatty acids vs placebo for 2 years improves
physical performance measures.
Methods: VITamin D and OmegA-3 TriaL (VITAL) was a double-blinded, placebo-controlled randomized trial of supplemental vitamin D3 and/or
omega-3 fatty acids vs placebo in the prevention of cancer and cardiovascular disease in 25 871 US adults. This ancillary study was completed in a
New England subcohort that had in-person evaluations at baseline and 2-year follow-up. This study was conducted with 1054 participants (age:
men ≥50 and women ≥55 years) at the Center for Clinical Investigations in Boston. Interventions included a 2 × 2 factorial design of supplemental
vitamin D3 (cholecalciferol, 2000 IU/day) and/or marine omega-3 fatty acids (1 g/day). Main outcome measures included 2-year changes in
physical performance measures of grip strength, walking speed, standing balance, repeated chair stands, and Timed-up and Go (TUG).
Results: At 2 years, all randomized groups showed worsening walking speeds and TUG. There were no differences in changes in grip strength,
walking speeds, Short Physical Performance Battery (composite of walking speed, balance, and chair stands), and TUG between the vitamin D3-
treated and the placebo-treated groups and between the omega-3-treated and the placebo-treated groups. Effects overall did not vary by sex, age,
body mass index, or baseline measures of total or free 25-hydroxyvitamin D (25[OH]D) or plasma omega-3 index; TUG slightly worsened with
vitamin D supplementation, compared to placebo, in participants with baseline total 25(OH)D levels above the median (P = .01; P for interaction = .04).
Conclusion: Neither supplemental vitamin D3 nor marine omega-3 fatty acids for 2 years improved physical performance in this generally healthy
adult population.
Key Words: vitamin D, omega-3 fatty acids, physical performance
Abbreviations: 25(OH)D, 25-hydroxyvitamin D; ALA, alpha-linolenic acid; ALM, appendicular lean mass; BMI, body mass index; CDC, Centers for Disease
Control and Prevention; CTSC, Clinical and Translational Science Center; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; EWGSOP2, European
Working Group on Sarcopenia in Older People 2; RCT, randomized controlled trial; SPPB, Short Physical Performance Battery; TUG, Timed-Up and Go;
VDR, 1,25-dihydroxyvitamin D receptor; VITAL, VITamin D and OmegA-3 TriaL.

Muscle mass, strength, and physical function decline with ad­
vancing age and are strongly associated with falls, fractures,
disability, hospitalization, and premature death (1, 2). While
lean mass contributes about 50% of body weight in young
adults, it makes up only 25% in adults aged 75 to 80 years
(3). Additionally, fast type II muscle fibers are converted to
slow type I muscle fibers with age, causing loss of muscle
power, impaired mobility, and disability (4).
Skeletal muscle expression of receptors for 1,25-
dihydroxyvitamin D (VDR) decrease with age (5), and
vitamin D deficiency has been associated with loss of type II
muscle fibers in older adults (6). In a randomized study, vita­
min D supplementation has been shown to increase intramyo­
nuclear VDR concentration and muscle fiber size in older,
mobility-limited women with low vitamin D status (6).
Cross-sectional and longitudinal observational studies suggest
an association between low serum 25(OH)D levels and re­
duced muscle mass, strength, and performance, including
walking speed (7, 8). These observational studies can be con­
founded by low sun exposure, reduced dietary intake, and

Received: 2 November 2023. Editorial Decision: 6 March 2024. Corrected and Typeset: 19 March 2024
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2 The Journal of Clinical Endocrinology & Metabolism, 2024, Vol. 00, No. 0
decreased physical activity among older adults. Several
randomized controlled trials (RCTs) have evaluated the effect
of vitamin D supplementation on physical performance meas­
ures, but results have been inconsistent (9-16).
Omega-3 fatty acids, both marine (eicosapentaenoic acid
[EPA] and docosahexaenoic acid [DHA]) and plant-based
(alpha-linolenic acid [ALA]), may also potentially improve
muscle function and strength via anti-inflammatory effects, in­
creased muscle protein synthesis, and reduced muscle protein
breakdown (17, 18). Data on the effects of supplemental
omega-3 fatty acids on muscle mass and physical performance
are sparse. A cross-sectional study from the National Health
and Nutrition Examination Survey (NHANES) 1999 to
2002 in 2141 older adults aged 50 to 85 years found that total
omega-3 intake was positively associated with knee extensor
strength in older men but not in older women (19). Another
cohort study in Iceland found that although higher polyunsat­
urated fatty acid intake was positively associated with in­
creased thigh muscle size and greater knee strength, total
omega-3 intake was not associated with muscle size or
strength (20). In addition, no associations between intakes
of polyunsaturated fatty acids or omega-3 fatty acids and
changes in muscle size or strength were found over 5 years
of follow-up. A meta-analysis of 10 RCTs (7 with marine
omega-3 supplements, 1 with ALA from flax oil, and 2 with
dietary pattern of omega-6 to omega-3 ratio <2) found that
omega-3 supplementation did have a small-to-moderate posi­
tive effect on muscle mass in 202 adults aged 60 years or older
and slightly improved performance on the Timed-Up and Go
(TUG) test in a total of 136 adults; no differences were seen in
walking speed or grip strength (21).
Given the conflicting and sparse literature, additional research
from large RCTs is needed to clarify the effects of vitamin D and
omega-3 supplementation on physical performance measures.
The VITamin D and OmegA-3 TriaL (VITAL) is a 2 × 2 factor­
ial, double-blinded, randomized, placebo-controlled trial
that found that supplemental vitamin D3 supplementation
(2000 IU/day) or marine omega-3 fatty acid (1 g/day), com­
pared to placebo, did not prevent cancer or cardiovascular dis­
ease overall, though supplemental omega-3 fatty acids did
reduce myocardial infarction risk, in 25 871 participants (22,
23). In this ancillary study to VITAL, we tested the randomized
effects of 2 years of supplementation with vitamin D3 and/or
omega-3 fatty acids, compared with placebo, on physical per­
formance measures in a subcohort of participants at the
Center for Clinical Investigations.
Materials and Methods
Trial Design
The parent VITAL investigated effects of supplemental vita­
min D3 supplementation (2000 IU/day) and/or omega-3 fatty
acid (1 g/day of Omacor containing 840 mg of marine
omega-3 fatty acids, including 460 mg of EPA and 380 mg
of DHA) on the primary prevention of cancer and cardiovas­
cular disease in women aged 55 years or older and men aged
50 years or older from all 50 US states. Exclusion criteria in­
cluded self-reported prior history of cancer (except nonmela­
noma skin cancer) or cardiovascular disease, hypercalcemia,
hypoparathyroidism or hyperparathyroidism, renal failure,
severe liver disease, sarcoidosis or other granulomatous dis­
ease, or other serious illness. In addition, participants com­
pleted a 3-month run-in period, during which they needed
to take at least two-thirds of placebo study pills to qualify
for randomization. During the run-in period and the interven­
tional trial, personal supplementation of vitamin D was lim­
ited to less than or equal to 800 IU daily and calcium was
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limited to less than or equal to 1200 mg daily; no supplemen­
tation of fish oil was permitted. A total of 25 871 participants,
including 5106 Black individuals, were treated for a median of
5.3 years (range, 3.8-6.1 years). The parent trial protocol has
been described in detail (24, 25), and the results of the parent
trial have been published (22, 23).
Participants within driving distance of Boston,
Massachusetts, and able to provide informed consent were re­
cruited for in-person clinical visits, including physical perform­
ance measures, anthropometric assessments, and blood draws,
at the Center for Clinical Investigations under the Harvard
Catalyst Clinical and Translational Science Center (CTSC) in
Boston. A total of 1054 VITAL participants completed baseline
visits, and retention rate at the 2-year follow-up was 92%. The
baseline visits were conducted between January 2012 and
March 2014, and the 2-year follow-up visits were completed
between January 2014 and July 2016. A total of 711 partici­
pants (67%) returned for 4-year follow-up visits.
Information on this study is available on the Clinical
Trials.gov website (NCT01747447). Pharmavite LLC do­
nated vitamin D and Pronova BioPharma of Norway and
BASF donated fish oil study pills and matching placebos in
the form of calendar packs. These ancillary studies were ap­
proved by the Partners Human Research Committees and
the institutional review board of Brigham and Women’s
Hospital. Patients provided written informed consent for
this ancillary study.
Physical Performance Measures
Physical performance was assessed at baseline and 2-year
follow-up and included grip strength, TUG, walking speed,
standing balance, and repeated chair stands. Grip strength,
which has been found to be inversely related to risk of falls
and hip fractures (26, 27), was tested by JAMAR Plus+
Digital Hand Dynamometer (Sammons Preston Rolyan). In
the TUG test, which also correlates with fracture risk (28,
29), participants were timed as they stood up from a chair,
walked 3 meters, turned around, and returned to sit in the
chair. Walking speed was assessed over 6 meters at normal
and fast paces. In addition to walking speed, standing balance
and repeated chair stands were also performed as part of the
Short Physical Performance Battery (SPPB, scored 0-12),
which is a validated measure of lower body function and pre­
dictive of recurrent falls (26, 30). For standing balance, partic­
ipants were asked to hold 3 basic standing positions
(side-by-side, semi-tandem, and full tandem [or heel-to-toe])
for 10 seconds each. For the chair stands, participants stood
and sat down 5 times with arms folded, using a standard
straight-backed chair (31). Of note, TUG and components
of the SBBP were added to the study protocol later; thus,
not every CTSC participant completed all physical perform­
ance measures at baseline. A total of 731 participants had as­
sessments of all physical performance measures, including
TUG, 766 completed all components of the SBBP, and all par­
ticipants performed grip strength at baseline. Measures of grip
strength, TUG, walking speeds, and chair stands were per­
formed twice at each visit, and the means were used for
analyses.
The Journal of Clinical Endocrinology & Metabolism, 2024, Vol. 00, No. 0
Measurement of Blood Samples
Blood samples were collected at baseline in all participants.
Serum total 25-hydroxyvitamin D (25[OH]D) levels were as­
sayed using liquid chromatography–tandem mass spectrom­
etry by Quest Diagnostics, and assays were calibrated to
standards of the Centers for Disease Control and Prevention
(CDC) (32). Free 25(OH)D levels were measured by a com­
petitive enzyme-linked immunosorbent assay 2-step immuno­
assay by Future Diagnostics Solutions B.V., developed in
collaboration with DIAsource ImmunoAssays S.A. (RRID:
AB_2890998). The coefficients of variation for the VITAL
samples were 4.9% and 6.8% for total and free 25(OH)D lev­
els, respectively. Plasma omega-3 index (EPA plus DHA as a
percentage of total fatty acids) was performed by liquid
chromatography–tandem mass spectrometry by Quest
Diagnostics. Quest Diagnostics performed the serum total
25(OH)D levels and plasma omega-3 indices at no cost to
the trial. Aside from the blinded assay analyses, Quest
Diagnostics and Future Diagnostics had no role in the study
design, data analysis, or manuscript preparation.
Statistical Analysis
We examined changes over time in physical performance
measures from baseline to year 2 post randomization in the
Harvard Catalyst CTSC cohort in an intention-to-treat
fashion.
To assess for balance among the randomized groups in this
subcohort, baseline characteristics were compared by treatment
assignment. T tests and analysis of variance (or the Wilcoxon
rank sum and Kruskal-Wallis tests if nonnormal) were used
to compare continuous variables, and chi-square tests were
used to compare proportions across randomized groups.
The primary analysis was the effect of supplemental vitamin
D3 or omega-3 fatty acid vs placebo on 2-year changes in the
measures of physical performance, adjusted for age and sex.
Proc mixed model was used with all measures as outcomes, in­
cluding baseline. We explored interactions between the inter­
ventions, as well as with the use of personal vitamin D
supplements and baseline biomarkers of serum total and
free 25(OH)D levels for vitamin D and dark-meat fish intake
and plasma omega-3 index for fish oil. In addition, we eval­
uated effect modification by age, sex, race, and body mass in­
dex (BMI).
Statistical analyses were performed using SAS 9.4 (SAS
Institute). P values less than .05 were considered statistically
significant. Statistical analyses in this ancillary study were
not adjusted for multiple hypotheses testing; secondary and
subgroup analyses should be interpreted cautiously.
Results
Ancillary Study Participants
A total of 1054 participants were recruited for the Harvard
Catalyst CTSC subcohort for physical performance measures.
Two-year follow-up was completed by 968 participants (92%
retention).
Table 1 shows the baseline characteristics of the CTSC sub­
cohort. Mean (±SD) age was 64.9 ± 6.5 years and 48.9%
were women. Mean 25(OH)D level was 28.1 ± 9 ng/mL,
and mean plasma omega-3 index was 2.9%. At baseline,
few participants had muscle weakness or low muscle perform­
ance, as defined by the European Working Group on
3
Sarcopenia in Older People 2 (EWGSOP2) (33). A total of
5.9% had low grip strength (<27 kg in men, <16 kg in wom­
en), 2.1% had slow completion of repeated chair stands of
more than 15 seconds, 1.9% had slow gait speed of 0.8 m/s
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or less, 1.3% had low SPPB score of 8 or less, and no partic­
ipants had a TUG time longer than 20 seconds.
As the CTSC subcohort had to travel and complete exten­
sive clinical assessments, the subcohort was younger and
healthier than the overall cohort of 25 871 participants, which
had a mean age of 67.1 ± 7.1 years (25). The CTSC subcohort
was also less racially/ethnically diverse, reflecting the geo­
graphic region, compared to the overall cohort, which was
20.2% Black.
Baseline characteristics were generally balanced between the
vitamin D and non–vitamin D-treated groups and between the
omega-3 and non–omega-3-treated groups (see Table 1).
Although there was no difference in mean BMI between vitamin
D and non–vitamin D groups, the omega-3–treated group had
slightly higher BMI than the non–omega-3-treated group but
the difference was small and of little clinical significance. There
was no difference in number of participants taking personal vita­
min D supplements at baseline (limited to ≤800 IU/day), and no
difference in serum total and free 25(OH)D levels among
randomized groups. There was also no difference in mean plas­
ma omega-3 index or dark-meat fish intake at baseline.
Over 2 years, total and free 25(OH)D levels increased from
mean (±SE) of 27.6 ± 0.40 ng/mL to 40.0 ± 0.41 ng/mL and
5.90 ± 0.09 pg/mL to 9.12 ± 0.10 pg/mL, respectively, in the
vitamin D–treated groups, while there were no changes in to­
tal and free 25(OH)D levels in the non–vitamin D-treated
groups (treatment effect P < .0001 for both). The plasma
omega-3 index increased from 2.97% to 4.32% at 2-year
follow-up in the omega-3-treated groups, with no differences
observed in the non–omega-3-treated groups (treatment effect
P < .0001).
Effects of Supplemental Vitamin D on Physical
Performance Measures
At 2 years, both vitamin D–treated and placebo-treated
groups had slightly slower normal walking speed (change of
−0.04 m/s; P < .001, and −0.05 m/s; P < .001, respectively)
and fast walking speed (change of −0.06 m/s; P < .001, and
−.07 m/s; P < .001, respectively) (Table 2). Participants also
took longer to complete the TUG test at 2-year follow-up
(0.40 seconds longer; P < .001, in the vitamin D group and
0.30 seconds longer; P < .001, in the placebo group) (see
Table 2).
There were no significant effects of supplementation with
vitamin D vs placebo on 2-year changes in grip strength
(P = .36 for men; P = .35 for women), normal walking speed
(P = .53), fast walking speed (P = .74), standing balance
(P = .24), repeated chair stands (P = .46), TUG times (P = .23),
or SPPB scores (P = .15) (see Table 2).
Effects also did not vary by sex, age (divided at median), and
BMI (divided at the median) (data not shown). Interventional
vitamin D, compared to placebo, improved standing balance
in participants who also took their own personal vitamin D
supplements (change of 0.15 and −0.41 seconds, respectively;
P = .04), but there were no between-group differences in
changes in standing balance in those who did not take person­
al vitamin D supplements (P = .94) and the interaction was
not significant (P for interaction = .18). Compared to placebo,
4 The Journal of Clinical Endocrinology & Metabolism, 2024, Vol. 00, No. 0

Table 1. Baseline characteristics of the clinic subcohort at baseline, according to randomized assignment

Vitamin D No vitamin D P Omega-3 No omega-3 P

(n = 520) (n = 534) (n = 527) (n = 527)

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Age, mean (SD), y 64.7 (6.3) 65.1 (6.6) .33 64.8 (6.5) 64.9 (6.4) .88
Female sex, No. (%) 256 (49.2%) 259 (48.5%) .81 260 (49.3%) 255 (48.4%) .76
Race, No. (%) .62 .39
White 429 (84.0%) 442 (84.8%) 429 (83.5%) 442 (85.3%)
Black 42 (8.2%) 46 (8.8%) 43 (8.4%) 45 (8.7%)
Other 40 (7.8%) 33 (6.3%) 42 (8.2%) 31 (6.0%)
BMI, mean (SD) 28.1 (5.3) 28.3 (5.4) .64 28.6 (5.4) 27.7 (5.1) .005
Current smoking, No. (%) 30 (5.8%) 27 (5.1%) .59 26 (4.9%) 31 (6.0%) .47
Alcohol use, No. (%) >.99 .61
Never 107 (22.0%) 110 (21.8%) 108 (21.9%) 109 (21.8%)
Rarely to < weekly 33 (6.8%) 33 (6.5%) 37 (7.5%) 29 (5.8%)
1-6 drinks/wk 196 (40.2%) 204 (40.4%) 191 (38.7%) 209 (41.9%)
Daily 151 (31.0%) 158 (31.3%) 157 (31.8%) 152 (30.5%)
MET, h/wk, median (interquartile range) 21.6 (7.2-38.4) 20.9 (7.2-36.3) .60 21.6 (7.8-38.9) 21.0 (6.9-36.9) .40
History of fragility fracture (%) 49 (9.4%) 46 (8.6%) .65 44 (8.3%) 51 (9.7%) .45
History of fall in last year, No. (%) 105 (27.7%) 112 (29%) .67 109 (28.2%) 108 (28.4%) >.99
Diabetes, No. (%) 57 (11%) 51 (9.6%) .44 51 (9.7%) 57 (10.8%) .54
Rheumatoid arthritis, No. (%) 13 (2.5%) 14 (2.6%) .70 12 (2.3%) 15 (2.8%) .16
General health, No. (%) .20 .14
Excellent 208 (42.6%) 184 (36.2%) 208 (41.7%) 184 (37.0%)
Very good 196 (40.2%) 231 (45.5%) 196 (39.3%) 231 (46.5%)
Good 76 (15.6%) 82 (16.1%) 84 (16.8%) 74 (14.9%)
Fair 8 (1.6%) 11 (2.2%) 11 (2.2%) 8 (1.6%)
Personal use of supplemental vitamin D, No. (%) 230 (44.2%) 247 (46.3%) .51 238 (45.2%) 239 (45.4%) .95
Baseline total 25(OH)D, ng/mL, mean (SD) 27.6 (8.8) 28.7 (9.3) .06 28.3 (9.5) 28.0 (8.6) .56
Baseline free 25(OH)D, pg/mL, mean (SD) 5.90 (1.85) 6.01 (1.94) .35 6.02 (2.02) 5.88 (1.75) .23
Dark-meat fish intake, servings/wk, median 0.93 (0.47-1.00) 0.93 (0.47-1.47) .36 0.93 (0.47-1.47) 0.93 (0.47-1.47) .34
(interquartile range)
Plasma omega-3 index, %, mean (SD) 2.93 (0.99) 2.96 (1.00) .60 2.97 (1.00) 2.92 (0.98) .34

Abbreviations: 25(OH)D, 25-hydroxyvitamin D; BMI, body mass index; MET, metabolic equivalent of task.

vitamin D supplementation worsened TUG times in partici­
pants with baseline total 25(OH)D levels greater than the me­
dian (P = .01), while there was no difference between vitamin
D–treated and placebo-treated groups in participants with
lower baseline total 25(OH)D levels (P for interaction = .04;
Table 3). In exploratory analyses, we found no correlation be­
tween TUG times and 25(OH)D levels at baseline (data not
shown). There was also a significant interaction (P = .003) be­
tween vitamin D intervention and baseline free 25(OH)D lev­
els (divided at the median) for grip strength in women (see
Table 3). Vitamin D supplementation, compared to placebo,
improved grip strength in female participants with baseline
free 25(OH)D above the median (P = .004), and vitamin D
supplementation seemed to worsen grip strength in women
with baseline free 25(OH)D levels less than the median
(P = .15). Due to the number of comparisons and the unex­
pected direction of the association (greater improvement
with supplementation among those above vs below the me­
dian), this could be a false-positive finding.
Among the 711 participants who had 4-year follow-up visits
at the Center for Clinical Investigations, vitamin D supplemen­
tation did not affect changes in physical performance measures
over 4 years, compared to placebo (data not shown).
Furthermore, there were no differences in 4-year changes in
TUG times between the vitamin D–treated and placebo groups
stratified by baseline 25(OH)D levels above and below the me­
dian (P = .22 and .91, respectively; P for interaction = .29).
Effects of Supplemental Omega-3 Fatty Acids
on Physical Performance Measures
Similarly, both omega-3-treated and placebo groups had
slightly slower normal walking speed (change of −0.05 m/s;
P < .001, and −.04 m/s; P < .001, respectively) and fast walk­
ing speed (change of −0.06 m/s; P < .001, and −.07 m/s;
P < .001, respectively) and longer TUG times (0.33 seconds
longer; P < .001, in the omega-3 group and 0.38 seconds lon­
ger; P < .001, in the placebo group) after 2 years (see Table 2).
There were no differences in effects of supplementation
with omega-3 fatty acids vs placebo on 2-year changes in
grip strength (P = .42 in men, P = .72 in women), normal
walking speed (P = .55), fast walking speed (P = .24), standing
balance (P = .16), repeated chair stands (P = .63), TUG tests
(P = .56), or SPPB scores (P = .82) (see Table 2).
The Journal of Clinical Endocrinology & Metabolism, 2024, Vol. 00, No. 0 5

Table 2. Effect of supplemental vitamin D and omega-3 fatty acids on physical performance measures, adjusted for age and sex

Vitamin D Omega-3

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n Active Placebo P, N Active Placebo P,
group group treatment group group treatment
effect effect

Grip strength, men, Baseline 533 40.00 ± 0.50 39.26 ± 0.49 533 40.44 ± 0.50 38.82 ± 0.49
mean ± SE, kg
2-y change 498 −0.24 ± 0.34 0.19 ± 0.33 .36 498 −0.21 ± 0.34 0.17 ± 0.33 .42
P .48 .57 .53 .62
Grip strength, Baseline 507 24.32 ± 0.30 23.91 ± 0.30 507 23.90 ± 0.30 24.33 ± 0.30
women, mean ±
SE, kg
2-y change 456 0.12 ± 0.23 −0.19 ± 0.23 .35 456 −0.09 ± 0.23 0.02 ± 0.23 .72
P .61 .42 .69 .92
Normal walking Baseline 989 1.23 ± 0.01 1.24 ± 0.01 989 1.23 ± 0.01 1.24 ± 0.01
speed, mean ±
SE, m/s
2-y change 909 −0.04 ± 0.01 −0.05 ± 0.01 .53 909 −0.05 ± 0.01 −0.04 ± 0.01 .55
P <.001 <.001 <.001 <.001
Fast walking speed, Baseline 818 1.79 ± 0.01 1.79 ± 0.01 818 1.78 ± 0.01 1.80 ± 0.01
mean ± SE, m/s
2-y change 747 −0.06 ± 0.01 −0.07 ± 0.01 .74 747 −0.06 ± 0.01 −0.07 ± 0.01 .24
P <.001 <.001 <.001 <.001
Standing balance, Baseline 823 29.31 ± 0.11 29.44 ± 0.11 823 29.55 ± 0.11 29.21 ± 0.11
median ± SE, s
2-y change 752 0.07 ± 0.15 −0.17 ± 0.14 .24 752 −0.19 ± 0.14 0.10 ± 0.14 .16
P .61 .25 .18 .51
Repeated chair Baseline 794 3.59 ± 0.03 3.64 ± 0.03 794 3.60 ± 0.03 3.63 ± 0.03
stands, mean ±
SE, s
2-y change 719 0.02 ± 0.03 −0.00 ± 0.03 .46 719 0.02 ± 0.03 −0.00 ± 0.03 .55
P .48 .74 .54 .82
TUG, mean ± SE, s Baseline 705 8.08 ± 0.06 8.08 ± 0.06 705 8.11 ± 0.06 8.05 ± 0.06
2-y change 648 0.40 ± 0.06 0.30 ± 0.06 .23 648 0.33 ± 0.06 0.38 ± 0.06 .56
P <.001 <.001 <.001 <.001
SPPB score, median Baseline 793 11.42 ± 0.04 11.50 ± 0.04 793 11.46 ± 0.04 11.45 ± 0.04
± SE
2-y change 717 0.05 ± 0.04 −0.04 ± 0.04 .15 717 −0.01 ± 0.04 0.01 ± 0.04 .82
P .29 .33 .90 .83

Abbreviations: SPPB, Short Physical Performance Battery; TUG, Timed-Up and Go.

Effects did not vary by sex (data not shown), age (data not
shown), BMI (data not shown), dark-meat fish intake (divided
at the median; Table 4), or baseline plasma omega-3 index
(divided at the median; see Table 4).
Omega-3 fatty acids supplementation did not affect changes
in the majority of the physical performance measures at 4-year
follow-up, compared to placebo (data not shown). The pla­
cebo group did have slightly better standing balance results
than the omega-3 group at 4 years (P for trend over time
= .01).
Finally, in exploratory analyses, the combination of vitamin
D and omega-3 supplementation for 2 years, compared to oth­
er treatment groups or double placebo, did not improve phys­
ical performance measures (data not shown), except for fast
gait speed. The combination of supplemental vitamin D and
omega-3 slowed the decline in fast gait speed (−0.04 ±
0.01 m/s; P = .01) compared to the other treatment
groups (−0.08 ± 0.01 m/s; P < .001; P for treatment effect
= .02).
Discussion
In this generally healthy adult population not selected for low
vitamin D levels or low fish intake, supplementation with
vitamin D3 and/or omega-3 fatty acids for 2 years did not
improve physical performance measures, compared to re­
spective placebos. Due to multiple comparisons, subgroup
analyses and secondary end points should be interpreted
with caution.
This VITAL ancillary study included participants who were
generally healthy midlife to older adults, and there were few
participants with muscle weakness or poor muscle perform­
ance, as delineated by EWGSOP2 (33). Furthermore, the
mean baseline 25(OH)D level of 28.1 ng/mL was likely
 6
Table 3. Changes in physical performance measures by vitamin D intervention vs placebo, stratified by baseline total and free 25(OH)D levels

Baseline total 25(OH)D level Baseline free 25(OH)D level

(n = 1053) (n = 1053)

<median (28 ng/mL) ≥median P for <median (5.9 pg/mL) ≥median P for
inter-action inter-
action
Vitamin D Placebo P, Vitamin D Placebo P, Vitamin D Placebo P, Vitamin D Placebo P,
group group treatment group group treatment group group treatment group group treatment
effect effect effect effect

Grip strength, Baseline 40.13 ± 0.67 38.58 ± 0.70 39.89 ± 0.77 39.93 ± 0.69 40.13 ± 0.68 38.49 ± 0.70 39.93 ± 0.74 40.06 ± 0.68
men, mean ±
SE, kg
2-y change −0.20 ± 0.48 0.76 ± 0.50 .17 −0.30 ± 0.48 −0.38 ± 0.43 .91 .27 0.01 ± 0.47 0.98 ± 0.48 .15 −0.57 ± 0.49 −0.64 ± 0.45 .92 .27
Grip strength, Baseline 24.29 ± 0.40 23.89 ± 0.45 24.40 ± 0.44 23.88 ± 0.40 24.70 ± 0.44 23.93 ± 0.45 24.01 ± 0.42 23.89 ± 0.41
women, mean
± SE, kg
2-y change −0.07 ± 0.33 0.22 ± 0.37 .56 0.28 ± 0.32 −0.41 ± 0.29 .11 .14 −0.71 ± 0.37 0.05 ± 0.38 .15 0.79 ± 0.28 −0.37 ± 0.28 .004 .003
Normal walking Baseline 1.23 ± 0.01 1.23 ± 0.01 1.24 ± 0.01 1.25 ± 0.01 1.23 ± 0.01 1.23 ± 0.01 1.24 ± 0.01 1.25 ± 0.01
speed, mean ±
SE, m/s
2-y change −0.05 ± 0.01 −0.05 ± 0.01 .61 −0.04 ± 0.01 −0.04 ± 0.01 .65 .95 −0.05 ± 0.01 −0.05 ± 0.01 .65 −0.03 ± 0.01 −0.05 ± 0.01 .16 .19
Fast walking Baseline 1.78 ± 0.02 1.77 ± 0.02 1.82 ± 0.02 1.80 ± 0.02 1.78 ± 0.02 1.76 ± 0.02 1.81 ± 0.02 1.81 ± 0.02
speed, mean ±
SE, m/s
2-y change −0.06 ± 0.01 −0.06 ± 0.02 .87 −0.07 ± 0.01 −0.08 ± 0.01 .66 .71 −0.06 ± 0.01 −0.05 ± 0.01 .55 −0.07 ± 0.02 −0.09 ± 0.01 .35 .32
Standing balance, Baseline 29.27 ± 0.16 29.32 ± 0.18 29.40 ± 0.16 29.55 ± 0.14 29.23 ± 0.16 29.33 ± 0.17 29.40 ± 0.16 29.52 ± 0.15
median ± SE, s
2-y change 0.21 ± 0.17 0.09 ± 0.19 .65 −0.10 ± 0.23 −0.37 ± 0.21 .40 .80 0.16 ± 0.19 −0.16 ± 0.20 .23 −0.03 ± 0.22 −0.16 ± 0.20 .64 .61
Repeated chair Baseline 3.58 ± 0.04 3.59 ± 0.05 3.61 ± 0.04 3.68 ± 0.04 3.61 ± 0.04 3.59 ± 0.04 3.58 ± 0.04 3.69 ± 0.04
stands, mean ±
SE, s
2-y change −0.02 ± 0.04 −0.02 ± 0.05 .93 0.07 ± 0.04 −0.01 ± 0.04 .19 .34 −0.02 ± 0.04 −0.00 ± 0.04 .80 0.06 ± 0.04 −0.02 ± 0.04 .16 .24
TUG, mean ± Baseline 8.22 ± 0.09 8.10 ± 0.10 7.93 ± 0.09 8.07 ± 0.08 8.24 ± 0.10 8.13 ± 0.10 7.92 ± 0.08 8.04 ± 0.08
SE, s
2-y change 0.30 ± 0.09 0.38 ± 0.10 .56 0.50 ± 0.07 0.25 ± 0.07 .01 .04 0.44 ± 0.08 0.36 ± 0.09 .49 0.36 ± 0.08 0.25 ± 0.07 .29 .90
SPPB score, Baseline 11.39 ± 0.06 11.43 ± 0.07 11.46 ± 0.06 11.56 ± 0.05 11.40 ± 0.06 11.43 ± 0.06 11.44 ± 0.06 11.57 ± 0.06
median ± SE
2-y change 0.03 ± 0.06 −0.03 ± 0.07 .49 0.06 ± 0.06 −0.06 ± 0.06 .19 .72 0.04 ± 0.06 −0.03 ± 0.06 .40 0.05 ± 0.06 −0.06 ± 0.06 .22 .81

Abbreviations: 25(OH)D, 25-hydroxyvitamin D; SPPB, Short Physical Performance Battery; TUG, Timed-Up and Go.
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Table 4. Changes in physical performance measures by omega-3 intervention vs placebo, stratified by baseline dark-meat fish intake and plasma omega-3 index

Baseline dark-meat fish intake Baseline plasma omega-3 index

<median (0.9 servings/wk) ≥median P for <median (2.7%) ≥median P for

inter-action inter-
action
Omega-3 Placebo P, Omega-3 Placebo P, Omega-3 Placebo P, Omega-3 Placebo P,
group group treatment group group treatment group group treatment group group treatment
effect effect effect effect

Grip strength, Baseline 39.49 ± 0.94 38.68 ± 0.83 40.44 ± 0.62 38.99 ± 0.65 40.72 ± 0.74 38.74 ± 0.68 40.27 ± 0.68 38.97 ± 0.72
men, mean ±
SE, kg
2-y change 0.28 ± 0.58 0.45 ± 0.51 .83 −0.19 ± 0.44 −0.03 ± 0.46 .80 .995 −0.59 ± 0.52 −0.04 ± 0.48 .44 0.06 ± 0.45 0.35 ± 0.46 .65 .78
Grip strength, Baseline 23.88 ± 0.44 24.52 ± 0.43 24.11 ± 0.43 24.27 ± 0.45 24.07 ± 0.42 24.19 ± 0.45 23.77 ± 0.43 24.38 ± 0.41
women, mean
± SE, kg
2-y change 0.08 ± 0.31 0.14 ± 0.30 .89 −0.21 ± 0.33 −0.06 ± 0.35 .76 .87 −0.13 ± 0.28 0.04 ± 0.31 .69 −0.11 ± 0.35 0.00 ± 0.33 .81 .98
Normal walking Baseline 1.22 ± 0.01 1.24 ± 0.01 1.24 ± 0.01 1.24 ± 0.01 1.21 ± 0.01 1.24 ± 0.01 1.24 ± 0.01 1.25 ± 0.01
speed, mean ±
SE, m/s
2-y change −0.05 ± 0.01 −0.04 ± 0.01 .65 −0.05 ± 0.01 −0.04 ± 0.01 .55 .95 −0.03 ± 0.01 −0.04 ± 0.01 .83 −0.06 ± 0.01 −0.05 ± 0.01 .33 .42
Fast walking Baseline 1.76 ± 0.02 1.77 ± 0.02 1.79 ± 0.02 1.83 ± 0.02 1.76 ± 0.02 1.76 ± 0.02 1.80 ± 0.02 1.84 ± 0.2
speed, mean ±
SE, m/s
The Journal of Clinical Endocrinology & Metabolism, 2024, Vol. 00, No. 0

2-y change −0.05 ± 0.02 −0.07 ± 0.02 .42 −0.06 ± 0.01 −0.07 ± 0.01 .40 .84 −0.06 ± 0.01 −0.05 ± 0.01 .81 −0.06 ± 0.01 −0.10 ± 0.01 .05 .12
Standing balance, Baseline 29.57 ± 0.19 29.16 ± 0.18 29.55 ± 0.15 29.23 ± 0.16 29.46 ± 0.18 29.13 ± 0.18 29.60 ± 0.14 29.28 ± 0.15
median ± SE, s
2-y change −0.12 ± 0.22 0.15 ± 0.21 .39 −0.24 ± 0.19 0.20 ± 0.20 .11 .73 −0.08 ± 0.23 −0.09 ± 0.22 .98 −0.29 ± 0.19 0.24 ± 0.19 .047 .19
Repeated chair Baseline 3.56 ± 0.05 3.63 ± 0.05 3.62 ± 0.04 3.64 ± 0.04 3.64 ± 0.05 3.59 ± 0.04 3.56 ± 0.04 3.67 ± 0.04
stands, mean ±
SE, s
2-y change 0.05 ± 0.05 −0.04 ± 0.05 .20 −0.00 ± 0.04 0.01 ± 0.04 .78 .24 −0.02 ± 0.04 −0.01 ± 0.04 .83 0.05 ± 0.04 −0.01 ± 0.04 .31 .40
TUG, mean ± Baseline 8.11 ± 0.10 7.96 ± 0.10 8.09 ± 0.08 8.16 ± 0.09 8.07 ± 0.10 8.05 ± 0.09 8.15 ± 0.08 8.04 ± 0.09
SE, s
2-y change 0.30 ± 0.08 0.46 ± 0.08 .16 0.34 ± 0.08 0.26 ± 0.08 .48 .13 0.39 ± 0.08 0.37 ± 0.08 .83 0.27 ± 0.08 0.39 ± 0.08 .31 .39
SPPB score, Baseline 11.44 ± 0.07 11.45 ± 0.06 11.49 ± 0.06 11.47 ± 0.06 11.47 ± 0.07 11.38 ± 0.06 11.46 ± 0.06 11.53 ± 0.06
median ± SE
2-y change 0.03 ± 0.07 −0.03 ± 0.06 .57 −0.03 ± 0.06 0.06 ± 0.06 .30 .27 0.01 ± 0.06 −0.00 ± 0.06 .92 −0.01 ± 0.06 0.01 ± 0.06 .81 .81

Abbreviations SPPB, Short Physical Performance Battery; TUG, Timed-Up and Go.
7

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8 The Journal of Clinical Endocrinology & Metabolism, 2024, Vol. 00, No. 0
sufficient for most health outcomes. Other RCTs have tar­
geted participants with low vitamin D status and/or functional
limitations. Two small RCTs suggested that older, frail wom­
en with low vitamin D status may derive the most benefit (15,
16). In an RCT in community-dwelling older women with
mean (±SD) baseline 25(OH)D of 17.7 ± 4.2 ng/mL, only
the weakest and slowest participants had significant improve­
ments in hip muscle strength and TUG times with vitamin D
supplementation (15). In another RCT in older women in
long-term geriatric care, vitamin D supplementation for 3
months improved musculoskeletal function (16). More recent
studies have not found a benefit for vitamin D supplementa­
tion on physical performance measures. An RCT in Black
women with 25(OH)D levels less than 30 ng/mL did not
find a benefit for vitamin D supplementation for 3 years on
SPPB, 6-minute walk test, or grip strength (34). Two recent
RCTs targeted older adults with low vitamin D status and
functional limitations but also did not find an effect of vitamin
D supplementation on physical performance measures (9, 35).
These trials were smaller and shorter in duration (≤12
months) compared to this ancillary VITAL study. The large
DO-HEALTH RCT in 2157 European adults aged 70 years
or older also did not find a benefit for 2000 IU/day of vitamin
D3 for 3 years on SPPB (36). Finally, a recent meta-analysis
published in 2021 suggested that vitamin D supplementation
may have adverse effects on muscle health, including de­
creased knee flexion strength and slower TUG time (37). In
VITAL, we observed longer TUG times in participants treated
with supplemental vitamin D with higher baseline total
25(OH)D levels, compared to placebo (P for interaction
= .04).
Our findings of no improvement in physical performance
with supplementation of omega-3 fatty acids were also con­
sistent with the findings from recent larger RCTs, including
the DO-HEALTH RCT (36). The Multidomain Alzheimer
Preventive Trial (MAPT) randomly assigned 1679 partici­
pants with mean age of 75 years to omega-3 fatty acids supple­
mentation (800 mg DHA and 225 mg EPA) alone, omega-3
fatty acids and multidomain intervention (including physical
activity, nutrition, and cognitive training), the multidomain
intervention plus placebo, or placebo for 3 years. In this trial,
omega-3 fatty acids supplementation also did not improve
physical performance, as assessed by repeated chair stands,
grip strength, walking speed, and SPPB, including in partici­
pants with low DHA + EPA erythrocyte level at baseline (38).
Our results were consistent with our recent findings that
vitamin D3 supplementation vs placebo did not improve meas­
ures of lean mass (lean mass index, appendicular lean mass
[ALM], and ALM/BMI) in a VITAL subcohort of 771 partic­
ipants who had body composition assessments by dual-energy
x-ray absorptiometry (39). Furthermore, we had also found
that vitamin D3 supplementation vs placebo did not decrease
risk of incident falls over 5.3 years in the overall VITAL cohort
of 25 871 participants (40). Finally, compared to placebo,
supplemental vitamin D or omega-3 fatty acids also did not af­
fect frailty score over 5 years, as assessed by annual question­
naires using the Rockwood frailty index, which includes
measures of function, cognition, mood, and comorbidities
(41). Similarly, the DO-HEALTH study also did not find a
benefit for vitamin D supplementation alone on falls or frailty,
according to Fried physical frailty phenotype (42, 43).
However, omega-3 fatty acid supplementation modestly re­
duced total falls by 10%, and the combination of vitamin
D3, omega-3 fatty acids, and exercise decreased odds of be­
coming prefrail (42, 43).
A major strength of this ancillary VITAL study is the size.
We had 1054 participants, allowing for subgroup analyses, in­
Downloaded from https://academic.oup.com/jcem/advance-article/doi/10.1210/clinem/dgae150/7629844 by Endocrine Society Member Access 3 user on 27 March 2024
cluding by baseline 25(OH)D levels and plasma omega-3 in­
dex. Total 25(OH)D levels were calibrated to CDC
standards, and free 25(OH)D levels were measured by
Future Diagnostics Solutions B.V. This study had high reten­
tion (92%). We also had excellent adherence, as indicated
by the increase in total 25(OH)D levels meeting the prespeci­
fied target of 36 ng/mL in the active intervention group. A
limitation was that some of the SBBP components and the
TUG test were initiated later in the interventional trial, so
not every participant in the CTSC subcohort had all physical
performance measurements assessed at baseline and 2 years.
As by trial design, VITAL was performed in a generally
healthy population with low rates of muscle weakness and
poor performance and few participants with low baseline
25(OH)D levels. As allowed by trial design, 46.3% of the par­
ticipants in the placebo group took their own personal vitamin
D supplements (limited to ≤800 IU/day) at baseline, along
with 44.2% in the active vitamin D group. Finally, a daily
dose of 2000 units of cholecalciferol may be considered mod­
erate to high, which was selected to achieve maximal efficacy
for the primary outcomes of the parent trial while maintaining
safety (44).
In a US population of midlife to older adults, not selected
for muscle weakness or function, low vitamin D levels, or
low fish intake, supplementation with vitamin D3 and/or
omega-3 fatty acids for 2 years did not improve physical per­
formance measures compared to placebo. These findings do
not support supplementation with vitamin D or omega-3
acids for muscular health in the general population. Along
with other findings from VITAL, these data suggest that pub­
lic health guidelines should recommend against vitamin D
supplementation for the prevention of adverse musculoskel­
etal health outcomes in healthy midlife to older adults.
Acknowledgments
We thank the trial participants, staff, and investigators. We
also thank the CDC (Drs Hubert Vesper and Julianne Cook
Botelho) for their collaboration on the standardization and
calibration of the total 25(OH)D measurements.
Funding
This work was supported by the National Institute of Arthritis
Musculoskeletal and Skin Diseases/National Institutes of
Health (NIAMS/NIH; grant Nos. R01 AR059775,
R01 AR070854, and R01 AR060574; PI, M.S..L). This re­
search was also supported by the VITAL parent grants and
U01 CA138962 and R01 CA138962 (PIs, J.E.M. and J.E.B.)
from the National Cancer Institute, the National Heart,
Lung, and Blood Institute, the Office of Dietary
Supplements, the National Institute of Neurological
Disorders and Stroke, and the National Center for
Complementary and Integrative Health. This work was con­
ducted with support from grants 1 UL1 RR025758 and 8
UL1 TR000170, the Harvard Clinical and Translational
Science Center, from the National Center for Research
Resources and by 1UL1TR001102. The content is solely the
responsibility of the authors and does not necessarily
The Journal of Clinical Endocrinology & Metabolism, 2024, Vol. 00, No. 0
represent the official views of the NIAMS, National Center for
Research Resources, the National Center for Advancing
Translational Science, or the NIH.
Disclosure
J.E.B. reports Pharmavite: other financial or material support.
The other authors have nothing to disclose.
Data Availability
Some or all data sets generated during and/or analyzed during
the current study are not publicly available but are available
from the corresponding author on reasonable request.
Clinical Trial Information
Clinical trial registration numbers NCT01747447 and
NCT01704859 (registered December 11, 2012).
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