Mohammad Hassan Murad, Khalid B. Elamin, Nisrin O. Abu Elnour, Mohamed B. Elamin, Aziz A. Alkatib, Mitra M. Fatourechi, Jaime P. Almandoz, Rebecca J. Mullan, Melanie A. Lane, Hau Liu, Patricia J. Erwin, Donald D. Hensrud, Victor M. Montori, The Impact of Vitamin D on Falls: A Systematic Evaluation and Meta-Evaluation, The Journal of Medical Endocrinology & Metabolism, Quantity 96, Situation 10, 1 October 2011, Pages 2997–3006, https://doi.org/10.1210/jc.2011-1193
Summary
Vitamin D exerts wide-ranging results, together with those who relate to bodily operate. This big selection of results is due, partially, to the truth that most tissues within the physique include receptors for 1,25-dihydroxyvitamin D. For instance, receptors within the muscle tissue might clarify the affiliation between vitamin D deficiency and myopathy, muscle weak point, and muscle ache (1). Correction of hypovitaminosis D by vitamin D administration can result in enchancment within the energy of the quadriceps muscle as measured by most voluntary contraction, maximal leisure charge, and different physiological muscle testing parameters, no matter whether or not sufferers had bone involvement or not (2). Thus, vitamin D supplementation might enhance useful outcomes, notably falls, that are related to important morbidity.
The Endocrine Society assembled a job drive of consultants to develop scientific observe tips relating to use of vitamin D. To help in formulating suggestions, we performed a scientific overview of the literature to quantitatively and qualitatively summarize the accessible proof relating to the impact of vitamin D supplementation on falls.
Supplies and Strategies
The report of this protocol-driven systematic overview adheres to the Most well-liked Reporting Gadgets for Systematic Evaluations and Meta-Analyses (PRISMA) assertion (3) and was accredited by the Vitamin D Process Pressure of The Endocrine Society. The standard of the collective physique of proof was rated utilizing the Grading of Suggestions Evaluation, Growth and Analysis (GRADE) strategies (4).
Eligibility standards
Eligible research had been randomized trials that enrolled grownup people who obtained vitamin D supplementation and a concurrent comparability group that didn’t obtain this intervention. We excluded research during which the intervention was calcitriol or one in every of its analogs. The first end result of curiosity was falls. Research had been included no matter their language, measurement, or period of affected person follow-up. Evaluation articles, commentaries, and letters that didn’t include unique knowledge and research that solely reported correlation of vitamin D ranges with outcomes with out offering a vitamin D-raising intervention to its contributors had been deemed ineligible.
Research identification
An skilled reference librarian designed and performed the digital search technique with enter from examine investigators with experience in conducting systematic opinions. To determine eligible research, we searched the digital databases: MEDLINE, EMBASE, Internet of Science, SCOPUS, PEDRO, Regional medical databases (KoreanMed, Scielo, LILACs, Imbiomed, Index for Australian medical literature, Jap Mediterranean Index, IndMed, ExtraMed) by way of August 2010. Search was performed utilizing medical topic heading phrases, textwords and key phrases based mostly on every database traits specializing in synonyms of vitamin D and a number of useful outcomes. We initially looked for different useful outcomes (high quality of life, ache, independence and actions of day by day dwelling); nevertheless, minimal and heterogeneous knowledge had been discovered. Subsequently, this report focuses on falls. A abstract of search technique is accessible within the Supplemental Knowledge (revealed on The Endocrine Society’s Journals On-line website online at http://jcem.endojournals.org). As well as, we reviewed the reference sections of eligible research and accessible opinions and requested doubtlessly eligible research from content material consultants.
Knowledge assortment
Groups of reviewers working independently and in duplicate used standardized types and screened all abstracts and titles and, upon retrieval of candidate research, reviewed the total textual content publications and decided examine eligibility. Disagreements about examine inclusion had been resolved by consensus (i.e. the 2 reviewers mentioned eligibility and reached an settlement). Reviewers extracted descriptive, methodological, and end result knowledge from all eligible research.
Knowledge collected from research included an outline of the inhabitants (e.g. age, intercourse, dwelling, comorbidities, and vitamin D standing), the intervention (the kind of vitamin D-raising intervention, dose, and route), examine design and high quality parts, and knowledge akin to the outcomes of curiosity. For dichotomous outcomes, a 2 × 2 desk was created from every examine, and if not accessible, probably the most adjusted abstract measure and confidence interval (CI) values had been used.
To evaluate the danger of fall, we thought of the variety of sufferers who suffered at the very least one fall because the occasion (end result) of curiosity. We didn’t use the variety of falls for this goal as a result of within-person correlation of the end result is excessive (i.e. few sufferers in a cohort will possible endure a lot of the falls), which can exaggerate the estimated threat. This assumption was examined in sensitivity evaluation. To lower the impact for reporting bias, we tried to contact the authors of all included research to find out whether or not any outcomes had been collected however not reported, and to make clear knowledge if wanted. Pairs of blinded reviewers assessed examine high quality. We evaluated allocation concealment, blinding, funding, and loss to follow-up.
Statistical evaluation
We used random impact meta-analysis (5) to pool odds ratios (OR) and 95% CI throughout included research. OR values underneath 1.00 are related to decreased threat for a specific end result because of vitamin D-raising intervention. The I2 statistic, which estimates the proportion of whole variation throughout research that is because of heterogeneity somewhat than likelihood, was used to evaluate heterogeneity (6). I2 values of 25 or much less, 50, and at the very least 75% signify low, reasonable, and excessive inconsistency, respectively. Therapy effect-subgroup interactions had been assessed by the ANOVA methodology and meta-regression evaluation. Publication bias was assessed by visually inspecting the funnel plot (se plotted vs. log OR) and statistically by conducting the Egger’s regression check to detect asymmetry of the plot. On this regression, the scale of the remedy impact is captured by the slope of the regression line, and bias is captured by the intercept. Statistical evaluation was performed utilizing Complete Meta-Evaluation (model 2, 2005; Biostat Inc., Englewood, NJ).
Subgroup and sensitivity analyses
To discover the causes of inconsistency and subgroup-treatment interactions, we outlined a priori subgroups based mostly on sufferers’ dwelling (group vs. institutionalized), vitamin D-raising intervention [oral vs. parenteral supplementation, calcium coadministration status, vitamin D type (D2 vs. D3)], and vitamin D dose (excessive vs. low; a number of definitions for “high” had been to be examined). Two reviewers independently categorized research as having a vitamin D-deficient inhabitants vs. not poor, based mostly on: 1) writer description of the inhabitants; 2) reported baseline serum degree of 25-hydroxyvitamin D [25(OH) D]; or 3) enrollment of sufferers with at the very least two vitamin D deficiency threat elements (aged age, darkish pores and skin, dwelling in a nursing residence, dwelling removed from the equator, winter season, sunscreen use, sporting a veil, smoking, weight problems, malabsorption illness, renal or liver illness, and use of medicine comparable to anticonvulsants, glucocorticoids, antirejection and HIV drugs) (7). We additionally assessed whether or not research that documented excessive adherence (>80%) or elevated serum degree of 25(OH) D had a considerably totally different remedy impact in contrast with research with low adherence or undocumented enhance of degree, respectively. We additionally assessed the impact of the size of examine follow-up as a steady impartial variable on the impact measurement. The impact of examine high quality on remedy impact was additionally evaluated. Excessive-quality research (during which allocation was hid and at the very least sufferers or suppliers had been blinded) had been in contrast towards decrease high quality research.
We performed sensitivity evaluation to find out whether or not examine conclusions are affected by alternative of: 1) meta-analysis methodology (random results mannequin vs. fastened impact mannequin); 2) the cutoff level that defines excessive dose of vitamin D (excessive dose was outlined as >800, ≥800, or >600 IU/d); and three) the definition of fall occasions (utilizing the “number of patients who suffered at least one fall” vs. utilizing the “number of falls”).
Outcomes
Research identification
We discovered 26 research that fulfilled eligibility standards. Determine 1 depicts the examine choice course of. Research enrolled 45,782 contributors that had been randomized to a type of vitamin D or a management intervention (imply age, 76 yr; 78% females; and median examine measurement, 604 contributors). Sufferers had a really excessive baseline threat of falling (15–69%; median, 50%). The period of vitamin D administration in these research ranged from 3–62 months (median, 12 months). κ statistic for interreviewer settlement on examine choice ranged from 0.70–0.80. We contacted the authors of twenty-two research (8–29) to verify collected knowledge and ask for added data/clarification if wanted. Desk 1 describes the included research. Twelve extra trials that assessed different useful outcomes comparable to ache and high quality of life had been discovered, however these trials had been markedly heterogeneous when it comes to their inhabitants, setting, and outcomes; therefore, they weren’t quantitatively pooled. The outline of their traits and their findings are introduced in Supplemental Desk 1.
Research high quality
Two research used cluster randomization, and clusters had been geographically outlined [separate parts of residential care facilities in one study (30) and outpatient public social service centers in the second study (31)]. Allocation was hid in 18 of 26 trials, and each sufferers and caregivers had been blinded in 18 of 26 trials. Loss to follow-up was not reported in 9 of 26 trials, and the proportion of sufferers misplaced to follow-up ranged from 0–52% with a imply of 10%. Funding included for-profit assets in 34% of research. κ statistic for interreviewer settlement on the totally different components of examine high quality ranged from 0.87–1.00. Desk 2 describes examine high quality.
Meta-analysis
Vitamin D was related to statistically important discount within the threat of falls (OR for the danger of struggling at the very least one fall, 0.86; 95% CI, 0.77–0.96; I2 = 66%; 26 research; Fig. 2). The I2 check signifies the presence of considerable statistical heterogeneity throughout research; thus, we carried out subgroup analyses to discover elements that will clarify the heterogeneity.
Desk 3 summarizes subgroup analyses. We discovered no important subgroup-effect interactions for analyses based mostly on sufferers’ dwelling (group dwelling vs. institutionalized), vitamin D route of administration (oral vs. parenteral), the kind of vitamin D-raising intervention (D2 vs. D3), examine high quality (excessive vs. low), adherence in intervention group (>80% vs. decrease adherence), or whether or not the examine documented a rise of 25(OH) D serum degree within the intervention group. The impact of examine period on fall threat was assessed by meta-regression, discovering no important affiliation (P = 0.16).
There was a big interplay when subgroups had been based mostly on sufferers’ vitamin D standing (poor vs. not poor), suggesting extra discount in falls in poor sufferers. Though we discovered no important sex-fall threat interplay throughout research, two research reported within-study subgroup evaluation demonstrating a bigger impact (extra discount within the threat of falls) in girls in contrast with males (10, 31). The inference from within-study comparability is stronger than between-study comparisons (32); subsequently, a bigger impact in girls is believable.
A statistically important interplay between the danger of fall and calcium coadministration standing was discovered (P = 0.01), suggesting that the discount within the threat of fall was larger when calcium was administered to each examine arms. The usage of a hard and fast impact mannequin as a substitute of random results mannequin didn’t change any of the examine conclusions. When the variety of falls (as a substitute of the variety of fallers) was used to evaluate the danger of fall, we additionally discovered a statistically important lower within the threat of falls related to administration of vitamin D (OR, 0.79; 95% CI, 0.70–0.88; I2 = 90%). Nevertheless, the discount in threat was extra pronounced, which is anticipated contemplating the within-person correlation of end result; and it was extra exact contemplating the bigger variety of occasions (falls). The exclusion of the 2 research during which cluster randomization was used didn’t change the examine conclusion relating to falls (OR, 0.80; 95% CI, 0.71–0.92). Altering the definition of “high dose” of vitamin D from larger than 800 IU/d to at the very least 800 IU/d or larger than 600 IU/d didn’t change the conclusion in regards to the lack of a statistically important dose-fall threat interplay. Lastly, the exclusion of 1 examine (20) with the best baseline threat of fall (stroke inhabitants) doesn’t change examine conclusions (OR, 0.88; 95% CI, 0.80–0.96; I2 = 62%).
Publication bias
The inspection of the funnel plot for the end result of falls suggests the presence of publication bias; i.e. empty quadrant during which doubtlessly small unpublished research might have proven much less discount in falls (Supplemental Fig. 1). Comparable inference is famous when Egger’s regression check is performed (intercept of −1.56; 95% CI, −2.41 to −0.65; P = 0.01, in line with the presence of publication bias). However, funnel plots could be deceptive, notably within the presence of considerable heterogeneity (33).
Dialogue
Foremost findings
We performed a scientific overview and meta-analysis to judge the perfect accessible analysis proof relating to the impact of vitamin D on falls. We discovered a statistically important discount within the threat of falls that was strong to sensitivity analyses. The discount in threat of falls seems to be extra outstanding in sufferers who had been poor in vitamin D. This inference is strengthened by the truth that even within the cohorts that we weren’t in a position to classify as possible vitamin D poor, an excellent proportion of contributors had been possible poor (e.g. sufferers had been aged and lived in northern climates, however the examine didn’t measure baseline vitamin D standing). Thus, the discount of falls famous in nondeficient cohorts might be attributed to undetected deficiency. Moreover, within-study comparisons in two research steered that the danger of falls may be extra pronounced in girls. Falls requiring medical consideration had been notably lowered by vitamin D alternative in girls in a single trial (OR, 0.72; 95% CI, 0.53–0.97) (34). Knowledge on high quality of life, ache, independence, and skill to carry out actions of day by day dwelling had been sparse. The discount in falls in research that didn’t coadminister vitamin D was not statistically important and was most pronounced in research that administered calcium to each examine arms.
The discount of falls related to vitamin D is biologically believable and could be defined by a number of mechanisms. Low serum 25(OH) D ranges are related to decreased muscle energy and drive (35). Vitamin D receptors are present in muscle tissue, and their activation results in muscle protein synthesis (36–38). This may occasionally contribute to decreased physique sway, improved muscle energy, and in the end, decreased propensity for falls (16, 36). The secondary hyperparathyroidism that develops from vitamin D deficiency can also play a task in rising the danger of falls. Hypophosphatemia, ensuing from excessive PTH ranges, might end in muscle weak point (35, 39). As well as, excessive ranges of PTH itself, which has been proven to have an effect on skeletal protein metabolism in animal fashions (40), has been related to poor muscle operate in some (2) however not all research (35, 41).
Limitations and strengths
Publication bias has possible affected the outcomes introduced on this overview. Though it’s tough to quantitatively assess for publication bias, statistical testing performed on this meta-analysis means that it has exaggerated the estimate of threat discount of falls. The presence of reasonable heterogeneity can weaken these conclusions about publication bias and decrease the general high quality of proof. As well as, sufferers on this overview had been at excessive threat of falls, as indicated by excessive charge of falls in management cohorts; thus, generalizing outcomes to different cohorts with decrease threat will additional downgrade the standard of proof as a consequence of indirectness. The dietary sources of vitamin D signify a cointervention that would introduce noise to the sign produced by the intervention in unblinded research and should bias the outcomes towards the null. On this case, most sufferers had been vitamin D poor, indicating that the dietary sources of vitamin D had been small in contrast with the dose given as an intervention; and the outcomes are unlikely biased because of the cointervention. Of notice, the sensitivity and subgroup analyses introduced on this report are study-level combination analyses; thus, inference about subgroup interactions is restricted by ecological bias and ought to be interpreted with warning. These limitations could be overcome by pooling particular person affected person knowledge to look at potential modifiers of remedy results (42).
The strengths of this overview stem from the in depth literature search, protocol-driven, reproducible nature of the overview, and the employment of bias safety measures comparable to reviewing articles and knowledge extraction by blinded pairs of reviewers.
Comparability with different opinions
Bischoff-Ferrari et al. (36) performed a meta-analysis that evaluated the consequences of vitamin D supplementation on falls that was up to date in 2009 (43). Our estimate of the danger of falls is much like theirs (OR of 0.84 vs. 0.87), which validates each estimates. Within the current report, nevertheless, extra sufferers are included (4-fold enhance in pattern measurement) as a result of the inclusion standards of Bischoff-Ferrari et al. (36) had been restricted to double-blind randomized-controlled trials with particular definitions of falls. The broader inclusion standards enable the analysis of heterogeneity and might solely introduce bias if fall ascertainment within the included trials was incomplete or inaccurate. We discovered no distinction in estimates between research of upper high quality and people with decrease high quality, validating the pooling process during which all research are mixed. We additionally tried to analyze the impact on different useful outcomes however discovered minimal knowledge.
Within the meta-analysis by Bischoff-Ferrari et al. (36), it was concluded that the discount in falls was solely noticed in research that used high-dose vitamin D. We didn’t discover such impact, which is in line with the reanalysis of Bischoff-Ferrari’s knowledge carried out within the Institute of Drugs report on vitamin D (44). That is additionally in line with one other trial (45) during which greater dose cholecalciferol remedy didn’t cut back falls in contrast with a decrease dose (2000 vs. 800 IU/d), suggesting no dose-response impact (28% discount; 95% CI, −4 to 68%).
Implications for observe and analysis
The present physique of proof helps a discount within the threat of falls attributable to vitamin D. The general high quality (threat of bias) of this proof is graded as reasonable because of the reasonable unexplained heterogeneity famous within the meta-analysis and the potential for publication bias. The suitable dose and period of vitamin D remedy, in addition to the goal inhabitants for this intervention are but to be absolutely outlined. The scientific observe tips doc from The Endocrine Society particulars the implications for clinicians and sufferers (53). Future trials ought to stratify contributors by the baseline threat for falls and check for distinction dosing regimens. The impact of supplementation on different useful outcomes must also be evaluated. Therefore, we encourage all future trials of vitamin D, no matter their goal or outcomes, to make use of standardized questionnaires and measure patient-important outcomes (46) comparable to high quality of life, different facets of bodily operate, and independence.
Conclusions
Vitamin D mixed with calcium reduces the danger of falls. The discount in research with out calcium coadministration didn’t attain statistical significance. The vast majority of the proof is derived from trials enrolling aged girls.
Abbreviations: – “vitamin d minder”
Acknowledgments
This overview was commissioned and funded by The Endocrine Society.
Disclosure Abstract: The authors (M.H.M., Ok.B.E., N.O.A.E., M.B.E., A.A.A., M.M.F., J.P.A., R.J.M., M.A.L., H.L., P.J.E., D.D.H., V.M.M.) don’t have anything to reveal.
References
“vitamin d minder”