What Comes Next for Vitamin D Supplementation and Trials in Older Adults?

Abstract

Vitamin D, or calciferol, is a fat-soluble hormone essential to many body functions. Naturally, it is present in some foods though it is largely synthesized endogenously through ultraviolet rays from sunlight exposure. Vitamin D deficiency has become increasingly common, and research studies have been undertaken to prove the benefits of vitamin D supplementation. However, benefits of vitamin D supplements have not been supported in rigorously conducted randomized controlled trials (RCTs) and meta-analyses [1-5]. Three recent RCTs have examined the role of vitamin D supplementation in community dwelling, generally healthy older adults: the American based VITAL (VITamin D and OmegA-3 TriaL), European DO-HEALTH (VitaminD3-Omega3-Home Exercise-HeALTHy Aging and Longevity Trial) [6], and Australian D-Health trial [7]. Each trial has been largely null for the role of supplemental vitamin D for primary outcomes of cardiovascular disease, cancer, fractures, and other health outcomes.

In this issue of the Journal, Eggimann et al. report post hoc findings from DO-HEALTH, a 2 × 2 × 2 factorial design RCT of vitamin D supplementation, omega-3 fatty acid supplementation, and home-based exercise programs for the prevention of incident sarcopenia and muscle loss in ambulatory community-dwelling healthy adults aged 70 years and older. Similar to the primary findings that supplementation with vitamin D did not impact incident nonvertebral fractures, functional decline, blood pressure, cognition, or infections, this secondary analysis did not find a protective effect of supplemental vitamin D on sarcopenia or muscle loss. Despite this, this study makes significant contributions to continue moving the field forward for research in this area and geriatric practice.

The results of this study have several implications for ongoing research in this area. First, even though epidemiological evidence has repeatedly demonstrated that low vitamin D levels are associated with multiple medical chronic conditions, including musculoskeletal health [8-11], results from RCTs have been disappointing. Are we targeting the wrong population, or must we provide higher dosages? Notably, currently established normal 25-hydroxyvitamin D (25(OH)D) levels may not apply to various population groups with different characteristics. The data remain unclear for specific populations such as those with obesity and Black Americans [12], populations requiring higher doses of vitamin D for adequate replenishment. Like any other trial, this study used one vitamin D supplementation dosage in all participants. However, heterogeneity in vitamin D responsiveness may dictate different dosages needed to show the benefits of vitamin D replacement in all study participants.

Another consideration regarding the benefits of vitamin D is the role of inflammation. Given longstanding evidence of mutually inhibitory effects between endocrine and immune/inflammatory pathways [13-16], heterogeneity of underlying inflammation or inflammaging may contribute to heterogeneity in responsiveness to vitamin D replacement. Inflammaging can be thought of as chronic, sterile, low-grade inflammation that occurs with aging and contributes to the pathogenesis of age-related chronic diseases. It is the long-term consequence of chronic stimulation of the innate immune system that becomes damaging during the aging process [17]. The interaction between inflammation and vitamin D may attenuate the effects of vitamin D supplementation on multiple clinical outcomes [14, 18]. Our previous studies in clinical settings have shown an interaction between inflammation (Interleukin-6 (IL-6) or C-reactive protein (CRP)) and low 25(OH)D levels in their association with slow gait speed, an essential indicator of muscle performance and sarcopenia [15, 16].

Whether or not inflammation affects the clinical outcome of interest even to a greater extent than vitamin D deficiency requires further research. Vitamin D deficiency is related to inflammation, which, in and of itself, has adverse effects on similar clinical outcomes. Low 25(OH)D levels were found to be causally related to CRP and it was suggested that replacement of vitamin D might correct inflammation [19]. In addition, inflammaging also causes vitamin D deficiency (Figure 1). If the influence of inflammation is more robust, correction of vitamin D deficiency alone without efforts to address co-existing inflammation might not yield satisfactory results, and this may be another explanation for unsuccessful results in proving the benefits of vitamin D supplementation in RCTs.

As a result, researchers need a novel perspective in designing future RCTs. Application of principles of Precision Medicine to geriatric patients (e.g., Precision Gerontology) [20, 21] may help unlock new insights and strategies for designing vitamin D supplementation RCTs by addressing heterogeneity of risk, particularly for participants who are most at-risk and therefore may be more likely to benefit. Whether 25(OH)D levels are a good indicator of vitamin D sufficiency and the same currently established normal 25(OH)D levels can be applied to all people is in question, considering differences in age group, sex, race and ethnicity, inflammatory state, and frailty levels, among others. Additionally, should every participant receive the same amount of vitamin D even though different groups of patients' characteristics would likely require different dosages of supplements? Research focusing on causal inference, including target trial emulation from large observational datasets, might provide clues for more effective designs for RCTs due to the size of data that allow sensitivity analyses for a more considerable extent than generally done in RCTs. A multidisciplinary approach, collaboration, and cross-talk between epidemiologic researchers and those involved in RCTs might be crucial in designing the most successful and cost-efficient RCTs.

As for geriatric practice, the study raised several questions that need to be addressed. Should lower than established normal 25(OH)D levels be the only indicator of supplementation, or should there be a single supplement dosage recommendation for everyone? Most trials that had the power to do the sensitivity analyses found no difference in the outcome regardless of the 25(OH)D levels before supplementation. However, in most trials, the participants with 25(OH)D levels checked before supplementation are only a tiny portion of the entire trial participants, thus increasing the risk of type II statistical errors. As described above, the study underscores precision gerontology's urgent and significant importance in geriatric practice. General recommendations to all individuals may not be the most beneficial approach to all older adults, even with a multidisciplinary approach with omega-3 supplementation and simple home exercise, as shown in the current study. The findings highlight the need for targeted interventions for older adults, which could be more effective in preventing sarcopenia and muscle loss. Although this has to be confirmed, the cost of interventions that offer no benefits could be diverted to other interventions that may benefit in this current medical world with issues of prioritization and allocation of limited resources.

In conclusion, what should a Geriatrician do? To answer this critical question definitively, we would need more studies with the most at-risk participants to confirm the benefits of vitamin D supplementation. The U.S. Preventive Services Task Force (USPSTF) recently released draft recommendation against vitamin D supplementation (grade D recommendation) for the primary prevention of falls and fractures in community-dwelling adults aged 60 years or older [22]. From current evidence, ambulatory community-dwelling older adults, even those above 70 years of age, such as those in this study, should not be given vitamin D supplements routinely for the purposes of preventing muscle loss or sarcopenia. On the contrary, using more individualized approaches, each clinician should make a clinical judgment on each individual depending on their risks. In contrast, individuals in long-term care facilities with other at-risk characteristics, including obesity, frailty, and certain race and ethnicity, may have a lower threshold of receiving vitamin D supplements than community-dwelling individuals. However, the risk still has to be considered individually.

J.K. wrote, reviewed, and prepared this editorial. A.O. reviewed and edited this manuscript.

The authors declare no conflicts of interest.

This publication is linked to a related article by Eggimann et al. To view this article, visit https://doi.org/10.1111/jgs.19266.