S.D. Anton1,2,*, R.T. Mankowski1,*, P. Qiu3, L. You4, B.A. Bensadon1, E.J. Audino1, C. Custodero1,5, J.H. Lee6, J. Hincapie1, C. McLaren1, C. Leeuwenburgh1, S.P. Ganesh7,8
1. Department of Aging and Geriatric Research, University of Florida, Gainesville, FL, USA; 2. Department of Clinical and Health Psychology, University of Florida, Gainesville, FL, USA; 3. Department of Biostatistics, University of Florida, Gainesville, USA; 4. Health Informatics Institute, University of South Florida, Tampa, USA; 5. Dipartimento Interdisciplinare di Medicina, Clinica Medica Cesare Frugoni, University of Bari Aldo Moro, Bari, Italy; 6. Department of Health Education and Behavior, University of Florida, Gainesville, FL, USA;
7. Physical Medicine and Rehabilitation Service, North FL/South GA Veterans Health System, USA; 8. Department of Occupational Therapy, University of Florida, Gainesville, FL, USA; *Both authors contributed equally to this paper.
Corresponding Author: Stephen D. Anton, Department of Aging and Geriatric Research, University of Florida, Gainesville, FL, USA, firstname.lastname@example.org; Tel.: +1 (352)-273-7514;
Fax: +1 (352)-273-5920
J Frailty Aging 2021;in press
Published online November 24, 2021, http://dx.doi.org/10.14283/jfa.2021.46
Background: Vitamin D insufficiency contributes to muscle weakness and a higher risk of falls in older adults.
Objectives: This study explored the impact of vitamin D supplementation on self-reported falls and physical function in older adults with low vitamin D levels and a recent fall history.
Materials and Methods: Twenty-five older adults ≥ 70 years with two or more falls during the past year, low vitamin D blood levels (≥10 ng/ml and < 30 ng/mL), and slow gait speed (1.2 m/s) participated in a 6-month vitamin D supplementation (800 IU/day) study. A modified version of the Morse Fall Scale questionnaire was used to assess frequency of falls over one-year prior to study enrollment. Functional outcomes (short physical performance battery, handgrip strength, gait Timed Up and Go, and six-minute walk), and vitamin D levels were assessed at baseline and 6-month follow-up.
Results: Based on diaries and pill counts, participants were generally adherent to the intervention (6 of 7 days per week). Supplementation with 800 IU/day of vitamin D for 6 months increased blood vitamin D levels from 23.25±4.8 ng/ml to 29.13±6.9 ng/ml (p<0.001). Self-reported number of falls decreased from an average of 3.76 ± 2.2 falls in one-year to 0.76 ± 1.4 falls (p <0.0001) over the 6-month intervention. No changes in functional outcome measures were observed.
Conclusions: Vitamin D supplementation at the currently recommended dose of 800 IU/day increased blood vitamin D levels and reduced frequency of falls in older adults with low vitamin D levels and a recent fall history.
Key words: Vitamin D, falls, older adults, feasibility, physical function.
Low vitamin D levels (< 30 ng/ml) affect approximately 40% of the general older adult population (1-5). Recent reports suggest that low vitamin D is both under-recognized and undertreated in older individuals (1, 2, 4). Vitamin D plays a crucial role in calcium homeostasis, which is critical for the maintenance of skeletal health. Older adults, especially those in more urbanized areas, often receive limited sun exposure and limited dietary intake of vitamin D (6-10). Low vitamin D levels can contribute to loss of physical function and unexplained falls in both men and women (3), partially due to decreased muscle strength and physical disability (11). Older women specifically experience increased body sway, risk for falls, and fall-related fractures, which may be due to an increased loss of bone mineral density following menopause (12, 13).
To date, the evidence is mixed regarding whether or not vitamin D supplementation can improve physical function and reduce frequency of falls. Manoy et al. reported improved handgrip strength, Timed Up and Go (TUG), 4-meter gait speed and the 6-min walk test in response to 6 months of high dose vitamin D (40,000 IU) supplementation per week in older adults with knee osteoarthritis and low baseline levels of vitamin D (< 30 ng/ml) (14). Conversely, other studies have shown that neither low nor high dose vitamin D supplementation improved physical function or reduced falls. Levis et al., reported that 9 months of high-dose vitamin D supplementation (4,000 IU) per day in older adults (65 – 90 years old) with baseline vitamin D levels < 30 ng/ml and short performance battery (SPPB) ≤ 9 did not improve SPPB and gait speed. However, a study of 12-month supplementation with 60,000 IU per month showed increased fall frequency and no change in SPPB compared to a lower dose of 24,000 IU per month (15).
Studies conducted specifically in women also presented mixed results. A study involving 6 months of low-dose supplementation (400 IU) per day was insufficient to improve muscle strength and physical function in older women (16). A study by Prince et al. included fall history during the 12 months prior to the study and oral intake of vitamin D (Ergocalciferol) at lower doses (1000 IU/day) and found a decrease in relative risk of falls over a one year period, but the population only included older women (17).
The inconsistent results in studies conducted to date could be due to variable dosing (high vs. low), participant sex (male vs. female), and inconsistent fall history inclusion criteria. Objective evidence is lacking for the effects of supplementation with the National Academy of Medicine’s recommended dose of 800 IU vitamin D in older adults with low levels of vitamin D and at least two falls in the past year (18). Therefore, we tested the feasibility of recruiting this target population of older men and women (>70 years of age) into a clinical trial evaluating whether vitamin D supplementation at the currently recommended dose of 800 IU/day could improve physical function outcomes and reduce fall occurrence over 6 months.
Materials and Methods
Participants were recruited through direct mailings. We enrolled individuals 70 years and older, with serum vitamin D levels > 10ng/ml and < 30 ng/ml, and with a recent history of falls (> 2 falls in the past year), and slow gait speed (< 1.2 m/s). This age cut off was selected because fall-related injuries and deaths are substantially higher over the age of 70, though the increase is less substantial in nonwhite populations (19). Participants with active diseases such as cardiovascular disease, cancer, diabetes, kidney and liver diseases, neurological conditions, and mental disorders were excluded to prevent the interference of these comorbidities with fall risk and functional outcomes. Additional comorbidities that can potentially affect the risk of falls included neurologic conditions such as peripheral neuropathy, dementia, and strokes as well as musculoskeletal conditions such as arthritis, particularly in the lower extremity joints (20); therefore, individuals who reported experiencing any of these conditions were excluded from participating in the study. Participants with vitamin D levels lower than 10 ng/mL or other abnormalities were referred to their primary care physician.
This study was approved by the University of Florida’s Institutional Review Board. All participants provided written informed consent to participate in this study.
The potential participants underwent an initial telephone screening to assess inclusion and exclusion criteria, which included medication, medical history and fall history. Potential participants were screened for the use of Vitamin D consumption, but not for all dietary supplements. Eligible participants who reported at least two falls over the past year and no major comorbidities were invited to the University of Florida’s Institute on Aging for a screening visit. During this visit, participants signed an informed consent before the initiation of study procedures. After informed consent was signed, participants provided their contact information and had their vitals measured. Mental state was assessed by the Mini-Mental Status Examination (MMSE) (21); all participants were required to score above a 24 on this measure to be eligible for this study. The participants self-reported their falls via the Morse Fall Scale (modified version) (22). Venous blood was drawn (approximately 150 ml) to measure the serum vitamin D levels.
After completing a baseline visit in which fall history and physical function were assessed, participants were provided with a three-month supply of capsules containing vitamin D (800 IU per capsule) and were instructed to consume one capsule per day and bring the remaining pills back to the clinic at their three-month follow-up visit. This supplementation dose was chosen based on the National Academy of Medicine’s recommendations (18).
Following their three-month assessment, participants were provided with another three-month supply of vitamin D capsules and were again instructed to follow the same dosing regimen and return the remaining pills to the clinic for a six-month follow-up visit. Adherence was assessed based on participant diaries and pill counts at 3 and 6-month follow-up visits.
Fall Frequency Assessment
Frequency of falls over the prior year was assessed with the Morse Fall Scale (modified version) (23). This scale consists of six variables that are simple to score and has been shown to have predictive validity and good interrater reliability for future falls (23). The tool was administered at screening, baseline, three-month assessment visit, and six-month post-treatment assessment visit. At the three and six-month visits, participants documented whether they had fallen since the prior visit, and whether falls required a visit to a doctor, emergency room, hospital, or urgent care center. We used the same questionnaire for all the visits.
Physical Function Assessments
The following physical function and upper-limb strength measures were conducted both at baseline and the six-month post-treatment assessment visit.
Timed Up and Go (TUG) test
The TUG measures the time that a person takes to rise from a chair, walk three meters, turn around, walk back to the chair, and sit down. During the test, the person is expected to wear their regular footwear and use any mobility aids (cane, walker or gait device) that they would normally require (24).
Six minute Walk
Participants were asked to walk as far and fast as possible for 6-min on a 40 m track. Participants were allowed up to two rest stops during the test.
Short Physical Performance Battery (SPPB)
The SPPB assessed functional performance on different tasks including tests of balance, gait speed, and repeated chair stands. Specifically, participants first performed balance tasks with their feet in side-by-side, semi-tandem, and tandem positions for 10 seconds each. Next, participants were asked to walk 4 meters at their usual pace. Finally, participants were asked to stand up from a chair and sit down five times as quickly as they could with their arms folded across their chest. Each task was scored from 0 to 4. The sum of the three subscales yields the total SPPB score, ranging from 0 (poorest function) to 12 (best function) (25).
Handgrip was measured by the Jamar Hydraulic Hand Dynamometer. This device was calibrated annually and was also checked monthly by study coordinators for accuracy. The participants were asked to squeeze a hand of the dynamometer as hard as they could twice. The tests were administered by a trained and certified study coordinator. The tests were conducted at baseline and 6-month follow-up.
Vitamin D Blood Level Measurement
Collected whole blood was processed by a phlebotomist for serum. Serum levels of vitamin D from the screening visit and at the six-month follow-up were analyzed by the liquid chromatography-tandem mass spectrometry performed by Quest Diagnostics Laboratories (Madison, NJ, USA).
Distribution of data was checked before analyses using histograms. We compared the relative frequency of falls (i.e., number of falls per month) prior to the baseline visit and over the 6-month follow-up period. The relative frequency of falls in the 6-month follow-up period is computed from the sum of recalled falls at the 3-month and 6-month follow-up visits. A Poisson mixed-effects model was used to examine whether there was a significant difference in the relative frequencies of falls reported over the two periods, adjusting for gender, baseline age, and baseline BMI. A similar Poisson mixed-effects model was used to compare the relative frequencies of falls reported at the 3-month and the 6-month follow-up visits. We then examined the change in walking speed, TUG, SPPB, and handgrip strength of both hands using linear mixed effects models with adjustment for baseline characteristics. Statistical significance was set at p<0.05. All analyses were conducted with SPSS software (V21) and R version 4.0.3.
Out of 1167 phoned-screened individuals, 107 were eligible for an in-person screening visit. After an in-person screening visit, 84 were excluded for various reasons including sufficient vitamin D levels (n=64), blood abnormalities (n=7), too low MMSE score (n=2), medical history (n=3), medication use (n=4), and other reasons (n=2) (Figure 1). Thus, a total of 25 older adults met the eligibility criteria and were enrolled in this open label six-month pilot study. Participants were on average 75.74 ± 4.93 years old, mostly female (60%) and white (88%). All other baseline characteristics and outcomes measures are summarized in Table 1.
The mean adherence level (percentage or prescribed product taken during the intervention period) was 82%, which means that participants took the supplement an average of 6 out of 7 days per week. This level of adherence is in line with reported medication adherence levels of older adults (26-28). All twenty-five enrolled participants completed the study. Supplementation with 800 IU/day of vitamin D for 6 months significantly increased the blood levels of vitamin D from 23.25±4.8 ng/ml to 29.13±6.9 ng/ml (p<0.001) (Figure 2).
Based on the Morse Falls Scale, the average number of falls recalled at baseline over the past one-year period was 3.76, and the average relative frequency was 0.313 falls per month. There were no reported falls that required a visit to a doctor, emergency room, hospital, or urgent care center. The average number of falls over the 6-month supplementation period was 0.76, and the average relative frequency was 0.132 falls per month. A Poisson mixed-effects model showed a significant difference in the relative frequencies of falls per month during the two periods (p<0.0001) after adjusting for baseline BMI, age and gender, as shown in Figure 3.
There was also a reduction in the average relative frequency of falls from 3-month assessment (0.146) to 6-month assessment (0.111), but the change was not significant after adjusting for age, gender and baseline BMI (p=0.515) (Figure 3).
Vitamin D supplementation did not significantly affect physical function outcomes. Baseline and 6-month follow-up measures of the six-minute walk test, TUG, SPPB, and handgrip strength results are summarized in Table 2. Changes in those measures are examined by linear mixed models adjusted for gender, baseline age and baseline BMI. No significant changes in physical outcomes are found. However, it is observed that baseline BMI is correlated with walking speed (r=-0.39, p=0.045), and males have higher handgrip strengths (Δ=13.44, p<0.0001).
This pilot study tested the feasibility of enrollment, adherence and the potential fall reduction of supplementation of vitamin D among older adults with low vitamin D levels and a recent fall history. The key finding of this study was that over a six-month period, supplementation with 800 IU/day of vitamin D significantly reduced the frequency of falls reported by older adults with low vitamin D levels (≥ 10 ng/ml and < 30 ng/ml) and a reported history of recent falls during the previous year. Additionally, there was a significant increase in blood levels of vitamin D from baseline to post-intervention.
Consistent with our findings, previous studies have reported vitamin D supplementation can reduce the frequency of falls in older adults with low vitamin D levels (< 30 ng/mL). A meta-analysis by Murad et al., which included 245 randomized controlled trials (originally 25 studies were included but Sato et al. was retracted), showed that vitamin D use between 600 IU and 800 IU per day, when combined with calcium supplementation, was associated with a significant reduction in fall risk among participants considered high risk at baseline (29). In line with our findings, the reduction in fall risk was larger in individuals who were vitamin D-deficient (< 30 ng/mL) in this meta-analysis (29). Another meta-analysis based on 5 double-blinded RCTs involving 1237 older adults (> 70 years old) with stable health and vitamin D levels lower than 30 ng/ml showed a 22% reduction in the reported number of falls after 400-1000 IU/day of vitamin D supplementation (2- 36 months) compared to participants who received calcium or placebo (17).
Somewhat surprisingly, none of the self-reported falls were injurious. This finding is likely due to the reduced rate of falls that occurred during the intervention period; each participant fell on average less than one time during the 6-month intervention supplementation period. It is also worth noting that this finding is in line with previous supplementation studies, which also found reductions in both the total number of falls and injurious falls among participants receiving vitamin D supplements for prolonged time periods (30, 31).
The potential mechanisms through which vitamin D supplementation may reduce the risk of falls in older adults
is not well-established; however, a few potential mechanisms have been proposed. One proposed mechanism is that vitamin D binds to specific receptors on skeletal muscle for 1,25-dihydroxyvitamin, which increases the relative number and cross-sectional area of fast-twitch muscle fibers (32). This skeletal-muscle related mechanism may contribute to better muscle function and strength (33), which can lead to decreased body sway, contra-balancing, and thus decrease susceptibility for falls (12, 29). Additionally, vitamin D has an important role in regulating calcium transport into muscle cells, which is required for muscle contraction (34). Vitamin D also helps regulate protein synthesis within muscle cells, which is needed to repair muscle fibers and for muscle cell growth (35, 36).
In addition to these potential mechanisms, there is increasing evidence that vitamin D plays a role in calcium uptake by the sarcoplasmic reticulum (37). Specifically, vitamin D deficiency has been found to reduce the rate of calcium reuptake in the sarcoplasmic reticulum following muscle contraction, which can result in muscle weakness (38). Since Vitamin D plays a critical role in the formation of energy-rich phosphate molecules, a deficiency in vitamin D can also reduce the energy available for muscle contractions (39). Finally, there is also increasing evidence that vitamin D levels can influence cerebral regulation of posture and balance, as vitamin D specific nuclear receptors have been found in cortical, subcortical, and spinal motor zones (33, 40).
Despite the reduced frequency of falls, we found no effect of vitamin D supplementation on objective measures of physical function measures or handgrip strength. The effects of vitamin D supplementation on changes in function have been mixed. Recent research aligns with our results that vitamin D supplementation does not lead to significant improvements in physical function (15, 41-43). For example, in a study by Ceglia and colleagues, 4 months of vitamin D supplementation increased intramyonuclear vitamin D receptor protein concentration by 30% and resulted in a 10% increase in total muscle fiber size. These changes, however, were not related to improvements on the knee extension test or SPPB (41). The findings of these studies suggest that vitamin D supplementation may reduce fall risk through mechanisms other than improved musculoskeletal function and warrant future investigation.
There were a few notable limitations of this study. First, a small sample size was included and followed for a relatively short time period. Second, there was no placebo comparison group. Thus, all participants were aware that they were receiving the study product, therefore we cannot exclude the possibility of a placebo effect. Third, this study was carried out over all seasons and we did not account for the potential effects seasonal changes may have had on Vitamin D levels. We also acknowledge that we do not know if fall opportunity changed during the intervention or if participants were more careful during the intervention and this was the reason for the observed reduction in falls. Finally, our primary outcome measure of falls was based on participant self-report, a subjective measure that may include some inaccuracies.
This study also had several strengths including use of objective methods to measure physical function and vitamin D status. We included older adults who self-reported at least 2 falls in the past year and were slow walkers. Reported adherence to the supplementation regimen was high and blood levels of vitamin D significantly increased over the course of the intervention.
In conclusion, 6-months of vitamin D supplementation significantly increased blood vitamin D levels and reduced the number of falls per month in vitamin D- deficient older adults with a recent history of at least 2 falls in the past year. These results warrant larger longitudinal and definitive studies to provide evidence based support for vitamin D supplementation leading to an increased fall risk prevention.
Vitamin D is one of the most important parameters to consider in geriatric practice. Aging associated physiologic and metabolic changes can potentially cause a progressive decline in the absorption of vitamin D and impair its function as a calcium binder in the bones (44). Common comorbidities such as chronic kidney disease, congestive heart failure, and even depression are potentially related to vitamin D deficiency. These comorbidities can contribute to the overall decline in patient well-being, and the presence of myalgias and progression of osteopenia towards osteoporosis, thereby increasing the risk for falls and fractures with progressive decline in physical function, as well as increasing health care costs and mortality rate (45).
Muscle impairment is commonly present in severely vitamin-D deficient individuals prior to biochemical indicators of bone diseases that may increase one’s risk of falls and/or fractures. One of the many reasons levels of vitamin D are an important parameter to consider in geriatric practice is that low vitamin D levels are especially prevalent in older adults with a history of fracture thus have important implications for bone health in the geriatric population (46). In line with this, a strong inverse relationship between low vitamin D levels and sarcopenia has been reported in an older adult population (47). As discussed above, vitamin D supplementation can have direct effects on muscle tissue, specifically through de novo protein synthesis which mediates muscle growth. For these reasons, vitamin D supplementation may be particularly important for vitamin-D deficient individuals to improve bone mineral density and reduce the likelihood of falls and fractures (48, 49).
Another common concern in older patients with a history of falls and vitamin D deficiency is the concomitant presence of polypharmacy. In particular, the use of standard medications including proton pump inhibitors, selective serotonin reuptake inhibitors, and anticonvulsants can potentially contribute to the reduction of vitamin D levels (50). A sedentary lifestyle and lack of sun exposure needed for the metabolic activation of vitamin D are also implicated as risk factors for vitamin D deficiency and associated fall risk (51). Further research is warranted to explore causality or possible secondary effects of other comorbidities, malnutrition and different socio-economic factors to vitamin deficiency.
Funding: This study was supported by 1 P30 AG028740-01.
Acknowledgments: We would like to thank the participants and the study staff for their efforts in completing this study.
Author Contributions: Christiaan Leeuwenburgh, Stephen Anton, conceived and designed the study; Robert Mankowski, Peihua Qiu, and Lu You analyzed the data; Stephen Anton and Robert Mankowski drafted the manuscript; Benjamin Bensadon, Carlo Custodero, Juhan Lee, Christian McLaren, Christiaan Leeuwenburgh and Elizabeth Audino edited the manuscript. Jacobo Hincapie and Shanti Ganesh provided feedback on the manuscript and wrote a clinical perspective section.
Conflicts of Interest: The authors declare no conflict of interest.
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