The Effect of Vitamin D on Falls: A Systematic Review and Meta-Analysis
Download the PDF here
J Clin Endocrin Metab. First published ahead of print July 27, 2011
Mohamed B. Elamin, Aziz A. Alkatib, Mitra M. Fatourechi, Jaime P. Almandoz, Mohammad Hassan Murad, Khalid B. Elamin, Nisrin O. Abu Elnour, Rebecca J. Mullan, Melanie A. Lane, Hau Liu, Patricia J. Erwin, Donald D. Hensrud, and Victor M. Montor Knowledge and Encounter Research Unit (M.H.M., N.O.A.E., M.B.E., A.A.A., M.M.F., J.P.A., R.J.M., M.A.L., P.J.E., V.M.M.), and Division of Preventive, Occupational, and Aerospace Medicine (M.H.M., D.D.H.), Mayo Clinic, Rochester, Minnesota 55905; Department of Medicine (K.B.E.), Case Western Reserve University, Metrohealth Medical Center, Cleveland, Ohio 44109; Division of Endocrinology, Diabetes, Metabolism, and Nutrition (V.M.M.), Mayo Clinic, Rochester, Minnesota 55905; and Division
of Endocrinology and Metabolism (H.L.), Santa Clara Valley Medical Center, San Jose, California 95128
"Implications for practice and research
The existing body of evidence supports a reduction in the risk of falls caused by vitamin D. The overall quality (risk of bias) of this evidence is graded as moderate due to the moderate unexplained heterogeneity noted in the meta-analysis and the possibility of publication bias. The appropriate dose and duration of vitamin D treatment, as well as the target population for this intervention are yet to be fully defined. The clinical practice guidelines document from The Endocrine Society details the implications for clinicians and patients (53). Future trials should stratify participants by the baseline risk for falls and test for difference dosing regimens. The effect of supplementation on other functional outcomes should also be evaluated. Hence, we encourage all future trials of vitamin D, regardless of their purpose or outcomes, to use standardized questionnaires and measure patient-important outcomes (46) such as quality of life, other aspects of physical function, and independence.
Conclusions Vitamin D combined with calcium reduces the risk of falls. The reduction in studies without calcium coadministration did not reach statistical significance. The majority of the evidence is derived from trials enrolling elderly women."
Context: Vitamin D affects bone and muscle health and likely reduces the risk of falls in the elderly.
Objective: The aim of this systematic review is to summarize the existing evidence on vitamin D use and the risk of falls.
Data Sources: We searched electronic databases from inception through August 2010.
Study Selection: Eligible studies were randomized controlled trials in which the intervention was vitamin D and the incidence of falls was reported.
Data Extraction: Reviewers working in duplicate and independently extracted study characteristics, quality, and outcomes data.
Data Synthesis: Odds ratio and associated 95% confidence interval were estimated from each study and pooled using the random effects model.
Results: We found 26 eligible trials of moderate quality that enrolled 45,782 participants, the majority of which were elderly and female. Vitamin D use was associated with statistically significant reduction in the risk of falls (odds ratio for suffering at least one fall, 0.86; 95% confidence interval, 0.77-0.96). This effect was more prominent in patients who were vitamin D deficient at baseline and in studies in which calcium was coadministered with vitamin D. The quality of evidence was low to moderate because of heterogeneity and publication bias.
Conclusions: Vitamin D combined with calcium reduces the risk of falls. The reduction in studies without calcium coadministration did not reach statistical significance. The majority of the evidence is derived from trials enrolling elderly women.
· Received April 7, 2011.
· Accepted July 7, 2011.
Vitamin D exerts wide-ranging effects, including those that relate to physical function. This wide range of effects is due, in part, to the fact that most tissues in the body contain receptors for 1,25-dihydroxyvitamin D. For example, receptors in the muscle tissue may explain the association between vitamin D deficiency and myopathy, muscle weakness, and muscle pain (1). Correction of hypovitaminosis D by vitamin D administration can lead to improvement in the strength of the quadriceps muscle as measured by maximum voluntary contraction, maximal relaxation rate, and other physiological muscle testing parameters, regardless of whether patients had bone involve ment or not (2). Thus, vitamin D supplementation may improve functional outcomes, particularly falls, which are associated with significant morbidity.
The Endocrine Society assembled a task force of experts to develop clinical practice guidelines regarding use of vitamin D. To assist in formulating recommendations, we conducted a systematic review of the literature to quantitatively and qualitatively summarize the available evidence regarding the effect of vitamin D supplementation on falls.
We conducted a systematic review and meta-analysis to evaluate the best available research evidence regarding the effect of vitamin D on falls. We found a statistically significant reduction in the risk of falls that was robust to sensitivity analyses. The reduction in risk of falls appears to be more prominent in patients who were deficient in vitamin D. This inference is strengthened by the fact that even in the cohorts that we were not able to classify as likely vitamin D deficient, a great proportion of participants were likely deficient (e.g. patients were elderly and lived in northern climates, but the study did not measure baseline vitamin D status). Thus, the reduction of falls
noted in nondeficient cohorts could be attributed to undetected deficiency. Furthermore, within-study comparisons in two studies suggested that the risk of falls might be more pronounced in women. Falls requiring medical attention were particularly reduced by vitamin D replacement in women in one trial (OR, 0.72; 95% CI, 0.53-0.97) (34). Data on quality of life, pain, independence, and ability to perform activities of daily living were sparse. The reduction in falls in studies that did not coadminister vitamin D was not statistically significant and was most pronounced in studies that administered calcium to both study arms.
The reduction of falls associated with vitamin D is biologically plausible and can be explained by several mechanisms. Low serum 25(OH) D levels are associated with decreased muscle power and force (35). Vitamin D receptors are found in muscle tissue, and their activation leads to muscle protein synthesis (36-38). This may contribute to decreased body sway, improved muscle strength, and ultimately, decreased propensity for falls (16, 36). The secondary hyperparathyroidism that develops from vitamin D deficiency may also play a role in increasing the risk of falls. Hypophosphatemia, resulting from high PTH levels, may result in muscle weakness (35, 39). In addition, high levels of PTH itself, which has been shown to affect skeletal protein metabolism in animal models (40), has been associated with poor muscle function in some (2) but not all studies (35, 41).
Limitations and strengths
Publication bias has likely affected the results presented in this review. Although it is difficult to quantitatively assess for publication bias, statistical testing conducted in this metaanalysis suggests that it has exaggerated the estimate of risk reduction of falls. The presence of moderate heterogeneity canweakenthese conclusions about publication bias and lower the overall quality of evidence. In addition, patients in this review were at high risk of falls, as indicated by high rate of falls in control cohorts;
thus, generalizing results to other cohorts with lower risk will further downgrade the quality of evidence due to indirectness. The dietary sources of vitamin
D represent a cointervention that could introduce noise to the signal produced by the intervention in unblinded studies and may bias the results toward the null. In this case, most patients were vitamin D deficient, indicating that the dietary sources of vitamin D were small compared with the dose given as an intervention; andthe results are unlikely biased due to the cointervention. Of note, the sensitivity and subgroup analyses presented in this report are study-level aggregate analyses; thus, inference about subgroup interactions is limited by ecological bias and should be interpreted with caution. These limitations can be overcome by pooling individual patient
data to examine potential modifiers of treatment effects (42).
The strengths of this review stem from the extensive literature search, protocol-driven, reproducible nature of the review, and the employment of bias protection measures such as reviewing articles and data extraction by blinded pairs of reviewers.
Comparison with other reviews
Bischoff-Ferrari et al . (36) conducted a meta-analysis that evaluated the effects of vitamin D supplementation on falls that was updated in 2009 (43). Our estimate of the risk of falls is similar to theirs (OR of 0.84 vs. 0.87), which validates both estimates. In the present report, however, more patients are included (4-fold increase in sample size) because the inclusion criteria of Bischoff-Ferrari et al . (36) were restricted to double-blind randomized-controlled trials with specific definitions of falls. The wider inclusion criteria allow the evaluation of heterogeneity and can only introduce bias if fall ascertainment in the included trials was incomplete or inaccurate. We found no difference in estimates between studies of higher quality and those with lower quality, validating the pooling procedure in which all studies are combined. We also attempted to investigate the effect on other functional outcomes but found minimal data.
In the meta-analysis by Bischoff-Ferrari et al . (36), it was concluded that the reduction in falls was only observed in studies that used high-dose vitamin D. We did not find such effect, which is consistent with the reanalysis of Bischoff-Ferrari's data performed in the Institute of Medicine report on vitamin D (44). This is also consistent with another trial (45) in which higher dose cholecalciferol treatment did not reduce falls compared with a lower dose (2000 vs. 800 IU/d), suggesting no dose-response effect
(28% reduction; 95% CI, 4 to 68%).
Implications for practice and research
The existing body of evidence supports a reduction in the risk of falls caused by vitamin D. The overall quality (risk of bias) of this evidence is graded as moderate due to the moderate unexplained heterogeneity noted in the meta-analysis and the possibility of publication bias. The appropriate dose and duration of vitamin D treatment, as well as the target population for this intervention are yet to be fully defined. The clinical practice guidelines document from The Endocrine Society details the implications for clinicians and patients (53). Future trials should stratify participants by the baseline risk for falls and test for difference dosing regimens. The effect of supplementation
on other functional outcomes should also be evaluated. Hence, we encourage all future trials of vitamin D, regardless of their purpose or outcomes, to use standardized questionnaires and measure patient-important outcomes (46) such as quality of life, other aspects of physical function, and independence.
Conclusions Vitamin D combined with calcium reduces the risk of falls. The reduction in studies without calcium coadministration did not reach statistical significance. The majority of the evidence is derived from trials enrolling elderly women.
We found 26 studies that fulfilled eligibility criteria. Figure 1 depicts the study selection process. Studies enrolled 45,782 participants that were randomized to a form of vitamin D or a control intervention (mean age, 76 yr; 78% females; and median study size, 604 participants). Patients had a very high baseline risk of falling (15-69%; median, 50%). The duration of vitamin D administration in these studies ranged from 3-62 months (median, 12 months). statistic for interreviewer agreement on study selection ranged from 0.70-0.80. We contacted the authors of 22 studies (8-29) to confirm collected data and ask for additional information/clarification if needed. Table 1 describes the included studies. Twelve additional trials that assessed other functional outcomes such as pain and quality of life were found, but these trials were markedly heterogeneous in terms of their population, setting, and outcomes; hence, they were not quantitatively pooled.
The description of their characteristics and their findings are presented in Supplemental Table 1.
Two studies used cluster randomization, and clusters were geographically defined [separate parts of residential care facilities in one study (30) and outpatient public social service centers in the second study (31)]. Allocation was concealed in 18 of 26 trials, and both patients and caregivers were blinded in 18 of 26 trials. Loss to follow-up was not reported in nine of 26 trials, and the proportion of patients lost to follow-up ranged from 0-52% with a mean of 10%. Funding included for-profit resources in 34% of studies. statistic for interreviewer agreement on the different elements of study quality ranged from 0.87-1.00. Table 2 describes study quality.
Vitamin D was associated with statistically significant reduction in the risk of falls (OR for the risk of suffering at least one fall, 0.86; 95% CI, 0.77-0.96; I2 = 66%; 26 studies; Fig. 2). The I2 test indicates the presence of substantial statistical heterogeneity across studies; thus, we performed subgroup analyses to explore factors that may explain the heterogeneity.
Table 3 summarizes subgroup analyses. We found no significant subgroup-effect interactions for analyses based on patients' dwelling (community dwelling vs. institutionalized), vitamin D route of administration (oral vs. parenteral), the type of vitamin D-raising intervention (D2 vs. D3), study quality (high vs. low), adherence in intervention group ( 80% vs. lower adherence), or whether the study documented an increase of 25(OH)Dserum level in
the intervention group. The effect of study duration on fall risk was assessed by meta-regression, finding no significant
association (P 0.16).
There was a significant interaction when subgroups were based on patients' vitamin D status (deficient vs. not deficient), suggesting more reduction in falls in deficient patients. Although we found no significant sex-fall risk interaction across studies, two studies reported withinstudy subgroup analysis demonstrating a larger effect (more reduction in the risk of falls) in women compared with men (10, 31). The inference from within-study comparison is stronger than between-study comparisons (32); therefore, a larger effect in women is plausible.
A statistically significant interaction between the risk of fall and calcium coadministration status was found (P= 0.01), suggesting that the reduction in the risk of fall was greater when calcium was administered to both study arms. The use of a fixed effect model instead of random effects model did not change any of the study conclusions.
When the number of falls (instead of the number of fallers) was used to assess the risk of fall, we also found a statistically significant decrease in the risk of falls associated with administration of vitamin D (OR, 0.79; 95% CI, 0.70-0.88; I2= 90%). However, the reduction in risk was more pronounced, which is expected considering the within-person correlation of outcome; and it was more precise considering the larger number of events (falls). The exclusion of the two studies in which cluster randomization was used did not change the study conclusion regarding falls (OR, 0.80; 95% CI, 0.71-0.92). Changing the definition of "high dose" of vitaminDfrom greater than 800 IU/d to at least 800 IU/d or greater than 600 IU/d did not change the conclusion about the lack of a statistically significant dose-fall risk interaction. Lastly, the exclusion of one study (20) with the highest baseline risk of fall (stroke population) does not change study conclusions (OR, 0.88; 95% CI, 0.80-0.96; I2 = 62%).