Effect of Vitamin D Supplementation, Omega-3 Fatty Acid Supplementation, or a Strength-Training Exercise Program on Clinical Outcomes in Older Adults: The DO-HEALTH Randomized Clinical Trial

Abstract

Importance: The benefits of vitamin D, omega-3 fatty acids, and exercise in disease prevention remain unclear.

Objective: To test whether vitamin D, omega-3s, and a strength-training exercise program, alone or in combination, improved 6 health outcomes among older adults.

Design, setting, and participants: Double-blind, placebo-controlled, 2 × 2 × 2 factorial randomized clinical trial among 2157 adults aged 70 years or older who had no major health events in the 5 years prior to enrollment and had sufficient mobility and good cognitive status. Patients were recruited between December 2012 and November 2014, and final follow-up was in November 2017.

Interventions: Participants were randomized to 3 years of intervention in 1 of the following 8 groups: 2000 IU/d of vitamin D3, 1 g/d of omega-3s, and a strength-training exercise program (n = 264); vitamin D3 and omega-3s (n = 265); vitamin D3 and exercise (n = 275); vitamin D3 alone (n = 272); omega-3s and exercise (n = 275); omega-3s alone (n = 269); exercise alone (n = 267); or placebo (n = 270).

Main outcomes and measures: The 6 primary outcomes were change in systolic and diastolic blood pressure (BP), Short Physical Performance Battery (SPPB), Montreal Cognitive Assessment (MoCA), and incidence rates (IRs) of nonvertebral fractures and infections over 3 years. Based on multiple comparisons of 6 primary end points, 99% confidence intervals are presented and P < .01 was required for statistical significance.

Results: Among 2157 randomized participants (mean age, 74.9 years; 61.7% women), 1900 (88%) completed the study. Median follow-up was 2.99 years. Overall, there were no statistically significant benefits of any intervention individually or in combination for the 6 end points at 3 years. For instance, the differences in mean change in systolic BP with vitamin D vs no vitamin D and with omega-3s vs no omega-3s were both -0.8 (99% CI, -2.1 to 0.5) mm Hg, with P < .13 and P < .11, respectively; the difference in mean change in diastolic BP with omega-3s vs no omega-3s was -0.5 (99% CI, -1.2 to 0.2) mm Hg; P = .06); and the difference in mean change in IR of infections with omega-3s vs no omega-3s was -0.13 (99% CI, -0.23 to -0.03), with an IR ratio of 0.89 (99% CI, 0.78-1.01; P = .02). No effects were found on the outcomes of SPPB, MoCA, and incidence of nonvertebral fractures). A total of 25 deaths were reported, with similar numbers in all treatment groups.

Conclusions and relevance: Among adults without major comorbidities aged 70 years or older, treatment with vitamin D3, omega-3s, or a strength-training exercise program did not result in statistically significant differences in improvement in systolic or diastolic blood pressure, nonvertebral fractures, physical performance, infection rates, or cognitive function. These findings do not support the effectiveness of these 3 interventions for these clinical outcomes.

Trial registration: ClinicalTrials.gov Identifier: NCT01745263.

Figure 1.. Flow of Participants in the DO-HEALTH Randomized Clinical Trial

Altogether, 1075 participants who received vitamin D were included in the primary analysis (21 had no follow-up, 105 had partial follow-up, and 12 died); 1081 who did not receive vitamin D were included (21 had no follow-up, 110 had partial follow-up, and 13 died); 1073 who received omega-3s were included (27 had no follow-up, 111 had partial follow-up, and 8 died); 1084 who did not receive omega-3s were included (15 had no follow-up, 104 had partial follow-up, and 17 died); 1081 who received strength-training exercise were included (17 had no follow-up, 108 had partial follow-up, and 11 died); and 1076 who received control exercise were included (25 had no follow-up, 107 had partial follow-up, and 14 died). ^aReasons for exclusion were as follows: 1268 unwilling to consent; 315 diagnoses of cancer (except nonmelanoma skin cancer, myocardial infarction, stroke, transient ischemic attack, or angina pectoris or history of coronary artery intervention); 280 unwilling to limit calcium supplements to ≤500 mg/d and vitamin D supplements to ≤800 IU/d and refrain from omega-3 supplements; 82 aged <70 years; 45 unable to swallow capsules; 34 not community dwelling; 31 participation in another clinical trial; 28 epilepsy and/or taking antiepileptic drugs; 20 hypercalcemia (serum calcium level >2.6 mmol/L); 18 insufficiently mobile; 15 living with a DO-HEALTH participant; 14 history of granulomatous disease (tuberculosis, sarcoidosis); 13 hypoparathyroidism/primary hyperparathyroidism; 11 Mini-Mental State Examination score <24 points; 6 major visual/hearing impairment; 4 severe renal impairment (creatinine clearance <15 mL/min); 3 severe liver disease; 3 fell more than 3 times in the last month; 2 hemiplegia or other gait impairment; 1 osteitis deformans (Paget disease); and 286 other reasons(medical condition that would make the results of the tests and assessments unreliable and/or would put too much burden on the participant and/or lead to safety concerns, eg, regular alcohol consumption and/or opioid abuse). ^bStratified block randomization on recruitment center, prior fall, sex, and age.

Figure 2.. Effects in the 8 Treatment Groups on Systolic Blood Pressure and Infections Over 3 Years

The 2 primary outcomes with the greatest intervention effects, systolic blood pressure and infections, were examined for combined intervention effects. A, Differences in systolic blood pressure are presented for the 8 randomized treatment groups (different from the treatment main effects results presented in Table 2) in the primary analysis, adjusted for the fixed effects of age, sex, prior fall, number of visit, body mass index, study site, and baseline systolic blood pressure. The plot shows differences of least-square means from a repeated-measures linear regression model with changes from baseline at 1, 2, and 3 years as outcomes compared with changes in the placebo group. B, Infections are presented for the 8 randomized treatment groups in the primary analysis, adjusted for the fixed effects of age, sex, prior fall, body mass index, study site, and offset of log person-years. The plot shows the incidence rate ratio per person-year from a Poisson regression model with infection count across 3 years as the outcome. Infections were assessed via questionnaire every 3 months and verified by an independent physician using all available information, including symptoms present, treatment received, and general practitioner diagnosis and hospitalization record, if available. ^aUnadjusted values. ^bAdjusted values.