Introduction

Vitamin D in conjunction with parathyroid hormone (PTH) regulates intestinal absorption of calcium, maintaining adequate concentrations for bone mineralization.1 Vitamin D deficiency is linked with bone metabolism disorders and reduced bone mineral density.2 More recently, vitamin D deficiency has been associated with the pathogenesis of several diseases including cardiovascular disease, some cancers and autoimmune diseases.3-5 Many experts report a major global pandemic of vitamin D deficiency and insufficiency, affecting one billion people worldwide.6-8 The major source of vitamin D is through exposure of the skin to ultraviolet-B (UV-B) radiation; few foods contain sufficient dietary vitamin D.6 Those at high risk of inadequate sunlight exposure and hence vitamin D deficiency include those living in a northern latitude, the institutionalised, elderly, and those who habitually avoid sun exposure for cultural or other reasons.2 In view of the high prevalence of vitamin D deficiency and the risk to musculoskeletal health, professional societies and government bodies worldwide have in the past decade issued dietary reference intakes (DRI) for vitamin D. The DRI for the general population over one year of age is 10 micrograms (mcg) a day in the UK, equivalent to 400 international units (IU), and 15 mcg (600 IU) in the USA and the rest of Europe.9-11

Vitamin D exists in two forms; vitamin D3 (cholecalciferol) is a fat-soluble vitamin that is mainly derived from 7-dehydrocholesterol upon exposure of the skin to UV-B radiation,1 and vitamin D2 (ergocalciferol) is found in only a few foods including fatty fish, egg yolk and fortified foods.1,2 The liver and kidneys convert vitamin D2 and D3 into the biologically active form of vitamin D, calcitriol (1,25 dihydroxyvitamin D [1,25-OHD]). The widely accepted measure of vitamin D nutrient status is via measurement of serum 25-hydroxyvitamin D (25-OHD) concentration12-13 because it has a longer half-life (2-3 weeks versus 4 hours) than the active form (1,25-OHD).1 In the adult population, serum 25-OHD concentration <12 ng/mL is considered deficient, 12-20 ng/mL insufficient and >20 ng/mL sufficient based on rickets prevention;10,14 however, there is considerable international debate on the definition and optimal serum levels of vitamin D.1,3,15

Several factors influence vitamin D status in the human body. These include the amount of vitamin D entering the body via sun exposure, skin pigmentation, latitude, and season; its absorption from the intestine; and its distribution in the body, as vitamin D is predominantly sequestered in adipose tissue.1,16,17 Vitamin D deficiency often occurs in people who are not exposed to sufficient sunlight, and in individuals with intestinal malabsorption disorders (e.g. inflammatory bowel disease or short bowel syndrome), the prevalence may be as high as 78%.9,18 Vitamin D supplements are available in a variety of over-the-counter and prescription strengths, in both ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3). Vitamin D3 is generally considered more potent than vitamin D212,14 and can be administered orally in solid forms such as tablets or capsules and as liquid preparations such as oral drops or via intramuscular (IM) injection. Vitamin D supplements are most frequently administered via the oral route as this is the most convenient and economic.14 Vitamin D in solid form, such as tablets or capsules, has a high degree of drug stability and provides accurate dosage.19 However, there are disadvantages to the oral route of administration. For example, there is variation in the extent to which patients can tolerate solid forms, particularly in the young and elderly and in those with impaired swallowing function.20,21 In patients with malabsorption, up to two to three times the usual amount of oral vitamin D may be required to achieve sufficiency.15,22 Additionally, the response to supplementation in malabsorptive disorders can be unpredictable.18,23,24

Vitamin D absorption occurs through a combination of passive diffusion and active transport mechanisms involving membrane carriers and cholesterol transporters.25,26 Vitamin D is lipid soluble and can be absorbed with long-chain triglycerides in the small intestine.27,28 Ingested vitamin D is incorporated into chylomicrons, which are released into the systemic circulation via the lymphatic system and then activated in the liver.29,30 Absorption studies indicate that individuals with malabsorption are 30-70% less likely to absorb oral vitamin D.24,31 The gastrointestinal tract is aqueous in nature; there is some evidence that vitamin D delivered in an oil-based formulation has improved solubility and ability to be incorporated into chylomicrons.32,33 A systematic review that evaluated the impact of different vehicles (powders, lipids, ethanol) on the absorption of vitamin D supplements reported that absorption was greatest in the oil-based vehicle.34 When the response to escalating doses of oral vitamin D supplements fails, IM vitamin D is an alternative. However, IM injections are associated with high inter-individual variability in absorption35 and slower onset of repletion.36 Additionally, an IM injection can be a painful procedure,20 and also requires a visit to a healthcare facility at one to three month intervals, adding to the administrative burden. There is interest in the potential of vitamin D supplementation in people with malabsorption via the buccal and sublingual mucosa of the oral cavity which is able to circumvent the gastrointestinal tract.21,37

Within the oral cavity is the oral mucosa comprising three main types: the lining mucosa of the inner cheeks (buccal mucosa); the sublingual region (floor of the mouth); and the masticatory mucosa, which comprises the lining of the upper surface of the mouth (the hard palate) and the gingiva (gums).20,38 Vitamin D is lipophilic (fat soluble), and sprays typically contain a solubilizing agent, such as oil in a micro-emulsified preparation and excipients including emulsifiers and permeation enhancers. This facilitates absorption across the oral membrane and into the systemic circulation, thus bypassing the gastrointestinal tract.20,38,39 Buccal spray delivery may result in a more effective route of administration and could reduce the burden associated with the IM route.38 To date, only one case study of sublingual vitamin D is identified in the literature, resulting in the correction of a vitamin D deficiency in an adult with Crohn's disease and end-ileostomy.40 However, a few studies have investigated buccal vitamin D spray in comparison to capsules or placebo, and in all of these, no safety concerns have been identified.41-43

In 2015, the first clinical trial of buccal spray vitamin D3 in humans was published. Satia et al.43 performed a two-way cross-over of buccal spray vitamin D3 versus equivalent dose vitamin D3 gel capsule in a study lasting 30 days per treatment arm with a 30-day washout in between. This study was conducted in an Indian population of healthy subjects, Indian patients with malabsorption and controls derived from both population groups. The study location was Gujarat, India, at a latitude which enables all-year-round skin synthesis of vitamin D. A daily regimen of 1000 IU buccal spray significantly increased mean serum 25-OHD concentrations as compared to the soft gelatin capsule, by 1.9 times in healthy adults (mean percentage increase from baseline, 43% vs. 22%, P < 0.0001) and 2.6 times in patients with intestinal malabsorption (118% vs. 36%, P < 0.005). However in the control groups, no significant changes were observed in serum 25-OHD levels (P-value not provided). In 2016, Todd et al.41 investigated a daily dose of 3000 IU buccal spray vitamin D3 versus vitamin D3 capsules in healthy participants (n = 22) in a randomized, two-way cross-over study. Conducted in wintertime in a northern latitude (Northern Ireland, UK), the supplement period lasted four weeks, with a 10-week washout between treatments. In comparison, the mean percentage increase for buccal spray vs. oral capsule was 44% and 51%, respectively (P = 0.313), indicating no significant difference between treatment groups.

Comparison between the study by Satia et al. and the present study shows that the efficacy of the spray was equivalent in the healthy groups (43% and 44%, respectively). However, there were notable differences in the percentage change for capsule supplementation (22% and 51%). The exact mechanism for this is unclear; however, Todd et al. postulated that ethnicity may in part explain these differences. Asian ethnicity is associated with reduced intestinal permeability.41,44 In 2017, Todd et al.42 used 3000 IU buccal vitamin D3 spray per day over a study period of 12 weeks and corrected vitamin D deficiency in athletes (n = 42) verses placebo spray (P = 0.006); however, the measurement of 25-OHD levels was a secondary endpoint. Following a preliminary search, no other directly relevant reviews on buccal spray vitamin D are available in the literature.

The primary objective of this review is to determine if there is enough evidence to conclude whether vitamin D supplementation via buccal spray is comparable in effectiveness to oral supplements, taken via the oral-gastric route. The secondary objective is to identify any adverse effects, as reported by the researcher. Safety is important to consider as treatments can be effective but are not useful if they have undesirable side effects. Effectiveness will be determined through evaluation of quantitative experimental studies using buccal spray vitamin D versus an oral comparator on measured serum 25-OHD levels. This will provide information on how the buccal spray compares in efficacy to another type of vitamin D supplement. It is anticipated that this information may help to inform clinical practice. We will consider experimental studies: randomized controlled trials (RCTs), crossover studies and controlled studies (quasi-experimental studies) in both adults and children with no restriction imposed on health status (i.e. healthy subjects or patient groups).

To our knowledge, this is the first review to have been conducted on the effectiveness of buccal spray vitamin D on serum 25-OHD levels. A search of the JBI Database of Systematic Reviews and Implementation Reports, Cochrane Database of Systematic Reviews, MEDLINE (Ovid), DARE, PROSPERO, Epistemonikos, and ACCESSSS on June 12, 2018, revealed no systematic or review paper on buccal spray vitamin D.

Inclusion criteria

A summary of the inclusion criteria can be found in Appendix I.

Population

This review will consider both children and adults with no restriction on age, gender, ethnicity or health status. Hospital inpatients, outpatients and community-dwelling individuals will be considered. In vitro or studies in animals are excluded. The purpose of the study is to evaluate the effectiveness of vitamin D supplementation via spray in humans. Findings from both the adult and pediatric population are relevant as they will provide important information regarding the effectiveness of buccal spray vitamin D delivery on serum vitamin D levels. In addition, no restriction is placed on the health status of the study population. In such an under-researched area, restricting the review to only select populations would exclude potentially relevant studies that address the research question. It may also highlight studies in which population groups were compared, which may facilitate sub-group analysis.

Intervention(s)

This review will consider studies that evaluate vitamin D supplementation of oral or buccal vitamin D spray (either vitamin D2 or vitamin D3) administered to the buccal mucosa. A preliminary scope of the literature reveals that the majority of studies use buccal vitamin D3 spray. Although most authorities advise that vitamin D3 is more effective than vitamin D2,12,14 restricting the review to vitamin D3 may potentially exclude relevant studies. In some studies, the term "oral spray" is used and in two studies, oral spray was administered to the buccal mucosa, which is the area of interest. Studies that supplemented individuals with oral spray vitamin D not specifically to the buccal membrane but to the mouth will be excluded, as the absorption of spray may be reduced on the surface of the tongue due to saliva. This review will also exclude studies using sublingual vitamin D supplementation, via spray or liquid, as there may be differences in the membrane permeability, which may not be comparable to the buccal route.20,38 Furthermore, only one study of sublingual vitamin D has been identified in a preliminary scope of the literature.40

Comparator(s)

We will consider for inclusion studies that compared the intervention to orally ingested vitamin D: vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol), at any dose, formulation, or duration. Comparing the intervention with all existing alternative interventions may help to identify its effectiveness against supplements that are conventionally prescribed. A sub-group analysis based on these different forms (i.e. vitamin D2 or vitamin D3) and formulations (i.e. tablet, capsule, liquid) will be considered. We will allow concomitant comparators (i.e. intervention and comparator vs. intervention). Comparing the intervention solely against a placebo was excluded as this may infer that buccal spray is beneficial when in fact it could be less effective than a conventional treatment, and therefore of no potential clinical benefit. Additionally, inclusion of a placebo group may undermine the potential for meta-analysis as it may positively skew the result in favor of the intervention.

Outcomes

The primary outcome is serum vitamin D levels as measured by 25-OHD level from baseline to follow-up measurement. Studies must report the change in 25-OHD from baseline to the end of the study or the pre-test and post-test result. We will include studies which report 25-OHD as nmol/L or ng/mL. For consistency, throughout the study, vitamin D will be reported as IU (1 IU = 0.025 [mu]g) and serum 25-OHD will be reported as ng/mL (1ng/mL = 2.5 nmol/L).9 No restriction will be placed on the methodology used to measure serum 25-OHD. Many laboratory methods are used to measure 25-OHD (e.g. liquid chromatography-tandem mass spectrometry, chemiluminescence immunoassay and enzyme linked immunosorbent assay). These differing techniques result in notable intra- and inter-assay variability.14 Internationally, there are efforts to standardize the measurement of vitamin D via the Vitamin D Standardization Program (VDSP); however, entry into this program is voluntary, and there is presently no obligation to abide with these standards.45

We will consider including studies of buccal spray vitamin D in which serum 25-OHD was measured as a secondary endpoint (surrogate outcome). The review question is to evaluate the effectiveness of buccal spray on serum 25-OHD levels and exclusion of studies using the spray in such an under-researched area could exclude potentially relevant studies.

The secondary outcome will be any reports of adverse effects, as reported by the researcher. Studies will not be excluded if they do not acknowledge adverse effects. In the event of non-disclosure of safety or adverse effects, researchers will be contacted to provide this information.

Types of studies

This review will include experimental study designs: randomized controlled trials (RCTs), crossover studies and quasi-experimental studies (non-randomized studies); RCTs are arguably the best study type to inform of clinical effectiveness.46 The crossover study, unlike a parallel group study, provides each participant with two or more sequential treatments in a random order that are usually separated by a washout period.47 With a crossover trial, each participant is able to act as his or her own control and permits between- and within-group comparisons. This type of study design avoids problems of confounding variables (i.e. latitude and dietary intake of vitamin D) and increases comparability,48 which in turn, may give more precise results than parallel group trials.49 Additionally, crossover studies can provide an understanding of the head-to-head comparative effectiveness of each of the treatments. Exclusion of lower methodological quality studies in which buccal spray was reported as a case study or case series is justified as these study types do not provide information on the comparative effectiveness of buccal spray as compared to vitamin D in an oral form. Furthermore, it may reveal that buccal spray was effective; however, it may be less effective than an existing treatment and therefore of no clinical benefit.

Methods

This systematic review will be conducted in accordance with the Joanna Briggs Institute (JBI) methodology for systematic reviews of effectiveness evidence.50

Search strategy

The search strategy aims to find both published and unpublished studies. Grey literature can make important contributions to a systematic review and can help to reduce the risk of publication bias i.e. from null or negative results.51 This will illustrate the full available research evidence and may identify gaps in the research base.52

A three-step search strategy will be utilized in this review. The initial search strategy and terms will be chosen in discussion with a medical librarian and information specialist with expertise in systematic review methodology. An initial limited search of MEDLINE and CINAHL will be undertaken followed by an analysis of the text words contained in the title and abstract, and of the index terms used to describe the article. A second search using all identified keywords and index terms will then be undertaken across all included databases. Thirdly, forward and backward citation searching will be conducted using the reference lists and citations of all identified reports and articles to search for additional studies.

No restriction will be placed on language. If required and if possible, we will use Google Translate53 to assist in translating non-English articles. This will ensure inclusivity of research despite the obvious limitations of online translation technology. To our knowledge, the first quantitative study to report on buccal spray vitamin D supplementation was in 2015. Studies published between 2008 to the present will be included. Extending the inclusion date to include 10 years is more likely to reflect current buccal spray formulations. If relevant, the reviewers intend to contact authors of primary studies for further information. A full search strategy for MEDLINE (Ovid) and CINAHL is detailed in Appendix II.

Information sources

A total of five databases will be searched: MEDLINE (Ovid), Embase (Ovid), CINAHL, AMED and Cochrane Library.

The search for unpublished studies (grey literature) will include: the Cochrane Handbook of grey literature databases, ProQuest Dissertation Publishing (PQDP) and the Google search engine using keywords relating to the research question.

Trial registers to be searched include: U.S. National Library of Medicine (ClinialTrials.gov) database; World Health Organization International Clinical Trials Registry Platform (ICTRP); All Trials (alltrials.net) and Restoring Invisible and Abandoned Trials (RIAT).

Study selection

Following the search, all identified citations will be collated and uploaded into Endnote X8 (Clarivate Analytics, PA, USA) and duplicates removed. Titles and abstracts will then be screened by two independent reviewers for assessment against the pre-defined (a priori) inclusion criteria for the review. Studies that meet the inclusion criteria will be retrieved in full and their details imported into the JBI System for the Unified Management, Assessment, and Review of Information (SUMARI) (Joanna Briggs Institute, Adelaide, Australia). Included studies will undergo a process of critical appraisal. The results of the search will be reported in full in the final report and presented in a Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flow diagram.54 Full-text studies that do not meet the inclusion criteria will be excluded, and reasons for exclusion will be provided in an appendix in the final systematic review report. Any disagreements that arise between the reviewers will be resolved through discussion or with a third reviewer.

Assessment of methodological quality

Papers selected for retrieval will be assessed by two independent reviewers for methodological validity prior to inclusion in the review using the following JBI critical appraisal tools: JBI checklist for randomized controlled trials50 and JBI checklist for quasi-experimental studies,50 as appropriate. All studies, regardless of their methodological quality, will undergo data extraction and synthesis (where possible). This is because the exclusion of studies of lower methodological quality could potentially reduce the number of includable studies and pool of evidence. Through assessment of methodological quality, it will be possible to illustrate the limitations of the research and therefore reduce the risk of publication bias. Any disagreements that arise will be resolved through discussion or with a third reviewer.

Data extraction

Data will be extracted from included papers using a customized tool which has been piloted (Appendix III). This includes information on the study design, study inclusion and exclusion criteria, study location and latitude, year/season the study was conducted, participant characteristics and mean baseline serum 25-OHD levels. Additionally, details of the intervention and dose, mean change in serum 25-OHD levels in each group, main findings and safety outcomes relevant to the review question will be included. All data will be subject to double data extraction by two independent reviewers. Two attempts will be made to contact the corresponding authors for missing information, where required.

Data synthesis

Data will be initially analyzed through a narrative synthesis method. During analysis, if a subset of data appears comparable, it may be possible to perform a meta-analysis. To be eligible for meta-analysis, a trial must report the mean change in 25-OHD levels from baseline for each trial group and the corresponding standard deviation or standard error. Where possible, quantitative data will be pooled in a statistical meta-analysis using JBI SUMARI.50 All results will be subject to double data entry. Effect sizes will be expressed as weighted mean differences (for continuous data) and their 95% confidence intervals (CIs) will be calculated for analysis. Relative risks and 95% CIs will be calculated for dichotomous data. Analysis of continuous data will be undertaken using the mean and standard deviation values to derive weighted mean differences (WMDs) and their 95% CIs.

Heterogeneity will be assessed statistically using the standard Chi-squared and I squared tests and also explored using subgroup analyses, i.e. buccal spray and comparator. If this indicates a high level of heterogeneity among the trials included in an analysis, a random effects meta-analysis will be performed for the overall summary. The choice of model (random or fixed effects) and method for meta-analysis will be based on the guidance by Tufanaru et al.50 Sensitivity analysis will be performed to test decisions regarding subgroup analysis. If 10 or more studies are included in a meta-analysis, a funnel plot will be presented, with the aims of assessing for signs of asymmetry with respect to publication bias. Statistical tests for funnel plot asymmetry (Egger test, Begg test, Harbord test) will be performed, where appropriate. Where statistical pooling is not possible, the findings will be presented in narrative format, including tables and figures to aid in data presentation, where appropriate.

Assessing certainty in the findings

The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach for grading the evidence will be followed in this review. A Summary of Findings will be created using GRADEpro GDT software (McMaster University, ON, Canada). The Summary of Findings will present the following information where appropriate: the absolute risks for treatment and control, estimates of relative risk and a ranking of the quality of evidence based on study limitations (risk of bias), indirectness, inconsistency, imprecision and publication. The following outcomes will be included in the Summary of Findings: change in serum 25-OHD levels (spray vs. oral comparator) and adverse events.

Acknowledgments

This protocol will contribute towards a Masters in Clinical Research (MClinRes) degree for author LP at the University of Plymouth.

The authors would like to acknowledge the following people for their assistance in the design of this protocol: Dr. Rebecca Abbott - Systematic Review Specialist, University of Exeter; Chris Johns - Information Specialist, University of Plymouth; and Dr. Steve Shaw - Senior Lecturer/Associate, University of Plymouth.

Funding

This research is funded by the National Institute for Health Research (NIHR) as part of the Masters in Clinical Research degree award program 2017-2018. The views expressed here are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.

Appendix I: Inclusion and exclusion criteria

Appendix II: Search strategies

MEDLINE (Ovid)

CINAHL

Appendix III: Piloted data extraction tool

Study design, setting and characteristics of participants of included studies

Study outcomes of included intervention studies

Figure. No caption available.

References