Key message
The NEJM (New England Journal of Medicine) has published the results of a additional research on the VITAL study. The VITAL trial is a large, randomized, placebo-controlled trial investigating vitamin D supplements or omega-3 fatty acids, or a combination of both, in the prevention of cancer and cardiovascular disease in men over 50 and women over 55 year [zie Folia juli 2022].1 An additional study analyzed the effect of vitamin D supplements (without calcium) on the incidence of fractures. According to this additional study, vitamin D supplementation without calcium did not reduce the risk of fractures (all types), non-vertebral fractures and hip fractures, compared to placebo, in healthy adults with an average age of 67 years.
Why is this study important?
Fractures, especially hip fractures, are a major public health problem. Moreover, in recent years, vitamin D has been linked, without much argument, to a protective effect in a variety of conditions, including COVID-19, reduced bone density and other diseases such as cancer and cardiovascular disease. In contrast, an RCT concluded that preventive vitamin D intake had no protective effect on overall mortality and no gains in cardiovascular and cancer mortality were seen. [zie Folia van juli 2022]. There are currently insufficient data to recommend or discourage the use of vitamin D in the treatment or prevention of patients with COVID-19 [zie Folia van januari 2021].2
Calcium and vitamin D are important for the formation and maintenance of bone tissue. This association without other medication provides slight protection in institutionalized elderly people, but it is insufficient in secondary prevention (ie after fracture) (see 9.5.1. Calcium).
A 2014 meta-analysis showed no benefit with vitamin D in monotherapy on the incidence of fractures (see Osteoporosis transparency sheet).3
Are there any new data on the effect of vitamin D supplementation in the prevention of fractures? The additional research to the VITAL study analyzed the effect in healthy adults with an average age of 67 years. What does this analysis teach us?
Design of the study
The additional study analyzed the effect of vitamin D supplementation on fracture risk compared to a placebo. This was a randomized controlled trial in which participants received vitamin D (colecalciferol) at a dose of 2,000 IU per day (without calcium), omega-3 fatty acids or a placebo.
The study included 25,871 patients (mean age 67 years), with a mean follow-up of 5.3 years. Participants were not selected based on vitamin D deficiency, low bone density or osteoporosis. At the start of the study, 42.6% of patients received vitamin D supplements (max 800 IU/d) and 20.0% received calcium supplements
(max 1 200 mg/d).
The VITAL study is a randomized controlled trial with a factorial design (protocol that is drawn up for a study that involves multiple interventions simultaneously evaluates).
The characteristics at the start were evenly distributed across the different groups. Average age 67.1 years. 50.6% women and 20.2% African Americans. 5% of patients used medication for osteoporosis and 2% used glucocorticoids. At baseline, 43% of patients used vitamin D supplements and 20% took calcium supplements. 10.3% of patients had a history of fragility fractures. After a run-in phase of approximately 3 months with placebo, participants were randomized who had taken at least two-thirds of the placebo tablets.
The primary endpoints were the incidence of new fractures (all types), non-vertebral fractures and hip fractures.
The participants self-reported the fractures using an annual questionnaire. Each reported fracture was assessed using the medical record and radiological images.
The secondary endpoints were the incidence of all types of fractures, non-vertebral fractures and hip fractures, excluding fractures of the toes, fingers, skull, periprosthetic fractures and pathological fractures.
Patients were randomly assigned to one of four groups:
Vitamin D (2,000 IU) and omega-3 fatty acids (1 g)
Vitamin D (2,000 IE) in placebo
Omega 3 fatty acids (1 g) and placebo
Double placebo
The additional study only evaluated the comparison of vitamin D with placebo. The comparison with omega-3 fatty acids was not included in the analysis.
Results in brief
Administration of vitamin D alone, without calcium, did not significantly reduce the risk of fractures (all types of fractures, non-vertebral fractures and hip fractures) compared to placebo in healthy adults, even after adjustment for age, gender, ethnicity and personal use of calcium supplements.
All types of fractures: in 769 out of 12,927 participants (6%) in the vitamin D group, versus 782 out of 12,944 participants (6%) in the placebo group (HR 0.98%, 95% CI 0.89 to 1. 08). Non-vertebral fractures: in 721 participants (5.6%) in the vitamin D group, versus 744 (5.7%) in the placebo group (HR 0.97%, 95% CI 0.87 to 1.07). Hip fractures: in 57 participants (0.4%) in the vitamin D group, versus 56 in the placebo group (0.4%)
(HR 1.01%, 95% CI 0.10 to 1.47). As far as the undesirable effects “hypercalcemia” and “kidney stones” were concerned, no difference was seen between the groups.
Limitations of the study
Only 1 dose of vitamin D (2,000 IU) and 1 route of administration (daily) were investigated.
Participants were not selected based on vitamin D deficiency, low bone density or osteoporosis. The results cannot be extrapolated to adults with osteoporosis, osteomalacia or institutionalized individuals.
Commentary from the BCFI
This research does not change the current message in the Repertory.
Calcium and vitamin D are important for the formation and maintenance of bone tissue.
Vitamin D supplementation (without calcium) is only recommended for patients at risk of vitamin D deficiency: pregnant women (especially dark-skinned and veiled women), the elderly (when insufficient exposure to outdoor light) and infants. Based on various studies, there are currently no arguments to recommend vitamin D supplementation outside the risk groups (see 14.2.1.2. Vitamin D and derivatives).
Sources
1 LeBoff, Meryl S., et al. “Supplemental vitamin D and incident fractures in midlife and older adults.” New England Journal of Medicine 387.4 (2022): 299-309.
2 Routine Supplemental Vitamin D Does Not Prevent New Fractures in Healthy Midlife and Older Adults, Study Finds, Worst Pills, Best Pills, 2023.
3 Avenell A, Mak JCS, O’Connell DL. Vitamin D and vitamin D analogues for preventing fractures in post‐menopausal women and older men. Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD000227. DOI: https://doi.org/10.1002/14651858.CD000227.pub4
2023-09-21 18:39:47
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