- Email: [email protected]
Topical vitamin D3: A randomized controlled trial (RCT)
Clinical Nutrition ESPEN xxx (2018) 1e4
Contents lists available at ScienceDirect
Clinical Nutrition ESPEN journal homepage: http://www.clinicalnutritionespen.com
Randomized Controlled Trial
Topical vitamin D3: A randomized controlled trial (RCT) Dalal A. Bubshait a, b, *, Dakheel A. Al-Dakheel a, b, Fawaz M. Alanii a, b a b
Department of Orthopaedic Surgery, College of Medicine, Imam AbdulRahman Bin Faisal University, Dammam King Fahd Hospital of the University, Al Khobar, Saudi Arabia
a r t i c l e i n f o
s u m m a r y
Article history: Received 26 February 2018 Accepted 22 May 2018
Objective: The intent of this study was to test the effect of Top-D, a topical Vitamin D preparation, in delivering vitamin D. Methods: Five hundred and fifty healthy patients, with vitamin D insufficiency and deficiency were recruited after written informed consent. Demographic data was recorded, adequate history and clinical examination was done to rule out any metabolic diseases. Complete blood picture, serum calcium, phosphorous, Parathormone and 25 Hydroxy-vitamin D3 (25OHD) was carried out before enrollment of the patients. Patients were divided randomly into two groups 350 in study group and 200 in the control group. Patients in the study group were given Top-D (Vitamin D3 gel made from proniosomal technology) to apply daily on the skin. Top-D 1 g contained 5000 IU of vitamin D3. The control group was given 1 g of Aloe vera gel to be applied every day. The two groups had no knowledge to which group they belong. After 4 months serum 25OHD was tested again. Results: Three hundred and forty five patients in study group and 192 in control group completed the study. The mean age of the patients in the both the groups was 42 years (18e80 years). The pretreatment 25OHD level in the study group was 11.03 ± 4.57 (2e12) ng/l compared to the control group 10.36 ± 4.09 (2e21) and post treatment the levels were 37.17 ± 6.04 (12e54) ng/ml and 10.51 ± 3.5 (2e19) ng/ml (p < 0.001). Conclusion: The results of this study indicate that transdermal route of vitamin D is potentially, safe and can give desired results to raise the vitamin D levels. This route is an alternate route for supplementation of vitamin D which should be utilized. © 2018 The Authors. Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).
Keywords: Vitamin D3 Topical use Supplementation deficiency Insufficiency
1. Introduction Vitamin D (VD) is one of the fat soluble vitamin which is important to maintain bone health and in prevention of rickets or osteomalacia in the adults. In majority of patients the Vitamin D deficiency or insufficiency occurs due to lack of sun exposure or due nutritional causes. Initial studies in 1980 showed that low level of vitamin D was common among Saudi Arabian population. Sedrani et al. (1983, 1984) [1,2] has shown that vitamin d deficiency existed irrespective of the season due to low exposure to the sunlight. Recent studies of Al-Turki et al. [3], Sadat-Ali et al. [4] found that about 60 percent of men and women in over 50 years of age had vitamin D deficiency but some studies put the deficiency of vitamin
* Corresponding author. King Fahd Hospital of the University, PO BOX 2208, Al Khobar, 31952, Saudi Arabia. E-mail address: [email protected] (D.A. Bubshait).
D to be 95e100% [5,6]. Added to this vitamin D Deficiency persisted even after prescription of vitamin D. One of the reasons that patients did not take medications as they were taking large number of oral medications daily [7 9]. It was reported that many of the oral medications prescribed are taken [10] and it was estimated for noncompliance of oral medications range between 62 and 84 percent [11,12]. hence we believe that in the young and elderly oral route can be avoided if topical route is available. The approval by the US FDA scopolamine as transdermal patch 40 years ago, the number of topical drug delivery increased [13 19]. Vitamin D is available in the form of tablets, drops and injection form and the compliance for oral VD and calcium was less than 60% [20 23]. Segal et al. (2009) [20] found that by end of 3 months, 23.8% of patients were taking properly and 26.2% more were partially compliant. It is our belief that if topical Vitamin D is available, the compliance might increase. This prospective RCT study was done to assess the outcome of topical delivery of VD.
https://doi.org/10.1016/j.clnesp.2018.05.009 2405-4577/© 2018 The Authors. Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism. This is an open access article under the CC BYNC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Bubshait DA, et al., Topical vitamin D3: A randomized controlled trial (RCT), Clinical Nutrition ESPEN (2018), https://doi.org/10.1016/j.clnesp.2018.05.009
2
D.A. Bubshait et al. / Clinical Nutrition ESPEN xxx (2018) 1e4 Table 1 Patients data. Parameter
Study Group
Control Group
Age (Years) Males Females Vitamin D level Pre Treatment (ng/mL) Vitamin D level Post Treatment (ng/mL)
42.59 ± 15.74 (18e80) 65 280 12.03 ± 4.57 (2e12) 37.17 ± 6.04 (12e54)
41.6 ± 16.6 (18e80) 55 137 10.36 ± 4.09 (2e21) 10.51 ± 3.5 (2e19)
2. Patients and methods
3. Results
The study was approved by the IRB of Imam AbdulRahman Bin Faisal University and funded by the Deanship of Scientific Research, Imam AbdulRahman Bin Faisal University, Dammam Saudi Arabia. An informed written consent was obtained from 550 healthy patients, with vitamin D deficiency and vitamin D insufficiency. Patients demographic data was collected. Complete history, thorough clinical examination was done to rule out any metabolic diseases. Blood was collected for complete blood picture, serum calcium, phosphorous, alkaline phosphatase, Parathormone and 25 Hydroxy-vitamin 3 (25OHD) levels. 25OHD3 was measured in King Fahd Hospital of the University, Alkhobar by chemiluminescence immunoassay (CLIA). A vitamin D3 level of 30 ng/mL was accepted as normal, 21e29 ng/mL as insufficiency and 20 ng/mL as deficiency. The patients were randomized into two groups of 350 in study arm and 200 in control arm. Participants were instructed not to change their dietary habits and increase sunlight exposure. Patients in the study group were given Top-D (Vitamin D3 gel made from proniosomal technology) to apply daily on the skin. Top-D 1 g contained 5000 IU of vitamin D3. The control group was given 1 g of Aloe vera gel to be applied every day. The two groups had no knowledge to which group they belong. After 4 months serum 25OHD was tested again. The data was analyzed using SPSS Inc version 19. The Study was monitored by the Monitoring Office for Research and Research Ethics (MORRE) of the Imam AbdulRahman Bin Faisal University, Dammam, Saudi Arabia. The study was registered with www.clinicaltrials.gov. (ClinicalTrials.gov Identifier: NCT02735200).
Three hundred and forty five patients in study group and 192 in control group completed the study. The mean age of the patients in the study group was 42.59 ± 15.74 (18e80) years and 41.6 ± 16.6 (18e80) years in control group. In the study group there were 65 males and 280 females, whereas in control group males were 55 and 137 females (Table 1). The pretreatment 25OH D3 level in the study group was 11.03 ± 4.57 (2e12) ng/mL compared to control group patients 10.36 ± 4.09 (2e21) (p < 0.9) and post treatment levels were 37.17 ± 6.04 (12e54) ng/mL and 10.51 ± 3.5 (2e19) ng/ mL (p < 0.001) (Fig. 1 and Fig. 2). In the study group 36 (10.28%) patients there was failure of vitaminD3 levels to reach above normal level. The level improved from 11.8 ± 4.86 to 20.78 ± 6.15 ng/mL (p < 0.001) (Fig. 3). In the study group 11 patients complained of initial irritation but decided to continue to be in the study. In the control group 7 patients had itching which subsided with time (Aloe-Vera). 4. Discussion The regular use of topical vitamin D3 (TOP-D) was effective in raising vitaminD3 levels within four months above the threshold of 30 ng/mL which was considered as normal levels in this study. The findings of this study is in line with results of the initial reported study [23]. Our study is the first clinical study of level II evidence which involved 345 patients. The justifications of developing a topical delivery of vitamin D are three-fold. The vitamin D deficiency and insufficiency is World wide, even in areas where sunlight is available all the year around and the benefits of vitamin
Fig. 1. Test group.
Please cite this article in press as: Bubshait DA, et al., Topical vitamin D3: A randomized controlled trial (RCT), Clinical Nutrition ESPEN (2018), https://doi.org/10.1016/j.clnesp.2018.05.009
D.A. Bubshait et al. / Clinical Nutrition ESPEN xxx (2018) 1e4
3
Fig. 2. Test group.
Fig. 3. Failure of treatment.
D has made people to go for supplements which are mainly of oral use. The low compliance of oral medications in general are well known and added to the absorption issues of oral vitamin D when improperly taken. The low absorption of vitamin D3 supplementation related to the type and quantity of food is incompletely understood. Raimundo et al. (2011) [24] recently reported the absorption was much better when supplementation was given with a high-fat meal. Patients are not given advice by the manufactures or physicians recommending vitamin D supplementation when to take. Secondly a topical delivery of vitamin D will be ideal for patients with chronic metabolic syndrome and with inflammatory bowel disease as their absorption is unpredictable leaving them with the side effects of hypovitaminosis D [25]. Lastly we believe that there is need of alternate route of vitamin D supplementation in patients post weight reducing surgeries in which there is an altered absorption of vitamin D [26]. Transdermal route for medications have been utilized since 1979 and at present many drugs from steroids to anti-inflammatory
and antibiotics are in routine use [27]. The development of proniosomal and nanotechnology revolutionized drug delivery systems particularly proniosomes due to ease in manufacturing, storage, absorption through the skin [28,29]. The size of the skin pores are approximately the diameter of 50 microns, whereas the average particle size of proniosomal Top-D gel is 3.84 ± 0.35 mm, hence the absorption of vitamin D3 through the pores was without difficulty. Even though ours was a RCT involving good number of patients, we did have a limitation of not performing the absorption studies, which could have strengthened the study robustly. We conclude that the topical delivery of vitamin D3 is achievable and can safely be used in patients particularly those oral absorption in doubt. Conflict of interest None declared.
Please cite this article in press as: Bubshait DA, et al., Topical vitamin D3: A randomized controlled trial (RCT), Clinical Nutrition ESPEN (2018), https://doi.org/10.1016/j.clnesp.2018.05.009
4
D.A. Bubshait et al. / Clinical Nutrition ESPEN xxx (2018) 1e4
Acknowledgement The authors thank Dean of Scientific Research, Imam AbdulRahman Bin Faisal University, Dammam for funding the project and Prof Mir Sadat-Ali and Dr Haifa A Al-Turki in planning the study and advice in completion of the trail. Appendix A. Supplementary data Supplementary data related to this article can be found at https://doi.org/10.1016/j.clnesp.2018.05.009. References [1] Sedrani SH, Elidrissy AW, El Arabi KM. Sunlight and vitamin D status in normal Saudi subjects. Am J Clin Nutr 1983;38(1):129e32. [2] Sedrani SH. Low 25-hydroxyvitamin D and normal serum calcium concentrations in Saudi Arabia: Riyadh region. Ann Nutr Metab 1984;28(3):181e5. [3] Al-Turki HA, Sadat-Ali M, Al-Elq AH, Al-Mulhim FA, Al-Ali AK. 25Hydoxyvitamin D levels among healthy Saudi Arabian women. Saudi Med J 2008;29(12):1765e8. [4] Sadat-Ali M, AlElq A, Al-Turki H, Al-Mulhim F, Al-Ali A. Vitamin D levels in healthy men in eastern Saudi Arabia. Ann Saudi Med 2009;29(5):378. [5] ElSammak MY, Al-Wossaibi AA, Al-Howeish A, Alsaeed J. Vitamin D deficiency in Saudi Arabs. Horm Metab Res 2010;42:1e5. [6] Al-Elq AM. The status of Vitamin D in medical students in the preclerkship years of a Saudi medical school. J Family Community Med 2012;19(2):100e4. [7] Grant AM, Avenell A, Campbell MK, McDonald AM, MacLennan GS, McPherson GC, et al. Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium or vitamin D, RECORD): a randomized placebo-controlled trial. Lancet 2005;365:1621e8. [8] Porthouse J, Cockayne S, King C, Saxon L, Steele E, Aspray T, et al. Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care. Br Med J 2005;330:1003e6. [9] Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006;354:669e83. [10] Avorn J. Medications and the elderly. In: Rowe J, Besdine R, editors. Geriatric Medicine. 2d ed. Boston: Little, Brown; 1988. [11] Kruse W, Koch-Gwinner P, Nikolaus T, Oster P, Schlierf G, Weber E. Measurement of drug compliance by continuous electronic monitoring: a pilot study in elderly patients discharged from hospital. J Am Geriatr Soc 1992;40: 1151e5. [12] Nikolaus T, Kruse W, Bach M, Specht-Leible N, Oster P, Schlierf G, et al. Elderly patients' problems with medication. An In-Hospital and Follow-Up Study. Eur J Clin Pharmacol 1996;49(4):255e9. [13] Thomas BJ, Finnin BC. The transdermal revolution. Drug Discov Today 2004;9: 697e703.
[14] Shi Y, Wei Z, Zhao H, Liu T, Dong A, Zhang J. Electrospinning of ibuprofenloaded composite nanofibers for improving the performances of transdermal patches. J Nanosci Nanotechnol 2013;13(6):3855e63. [15] Derry S, Moore RA. Topical capsaicin (low concentration) for chronic neuropathic pain in adults. Cochrane Database Syst Rev 2012;12:9. https://doi.org/ 10.1002/14651858.CD010111. CD010111. [16] Aggarwal N, Goindi S. Preparation and in vivo evaluation of solid lipid nanoparticles of griseofulvin for dermal use. J Biomed Nanotechnol 2013;9(4): 564e76. [17] Ahad A, Al-Jenoobi FI, Al-Mohizea AM, Aqil M, Kohli K. Transdermal delivery of calcium channel blockers for hypertension. Expert Opin Drug Deliv 2013;10(8):1137. [18] Goodman MP. Are all estrogens created equal? A review of oral vs. transdermal therapy. J Womens Health (Larchmt) 2012;21(2):161e9. [19] Morrow DIJ, McCarron PA, Woolfson AD, Donnelly RF. Innovative strategies for enhancing topical and transdermal drug delivery. Open Drug Deliv J 2007: 36e59. [20] Segal E, Zinman C, Raz B, Ish-Shalom S. Low patient complianceea major negative factor in achieving vitamin D adequacy in elderly hip fracture patients supplemented with 800IU of vitamin D3 daily. Arch Gerontol Geriatr 2009;49(3):364e7. s X, Ferrer M. Treatment persistence and compliance [21] Castelo-Branco C, Corte with a combination of calcium and vitamin D. Climacteric 2010;13(6): 578e84. s J, Gil-Guille n VF, Orozco-Beltran D, Giner-Ruiz V, Pertusa[22] Sanfelix-Genove Martínez S, Reig-Moya B, et al. Determinant factors of osteoporosis patients' reported therapeutic adherence to calcium and/or vitamin D supplements: a cross-sectional, observational study of postmenopausal women. Drugs Aging 2009;26(10):861e9. [23] Sadat-Ali M, Bubshait DA, Al-Turki HA, Al-Dakheel DA, Al-Olayani WS. Topical delivery of vitamin d3: a randomized controlled pilot study. Int J Biomed Sci 2014;10(1):21e4. [24] Raimundo FV, Faulhaber GA, Menegatti PK, Marques Lda S, Furlanetto TW. Effect of high- versus low-fat meal on serum 25-hydroxyvitamin D levels after a single oral dose of vitamin D: a single-blind, parallel, randomized trial. Int J Endocrinol 2011. https://doi.org/10.1155/2011/809069. [25] Farraye FA, Nimitphong H, Stucchi A, Dendrinos K, Boulanger AB, Vijjeswarapu A, et al. Use of a novel vitamin d bioavailability test demonstrates that vitamin D absorption is decreased in patients with quiescent crohn's disease. Inflamm Bowel Dis 2011. https://doi.org/10.1002/ ibd.21595. [26] Bland CM, Quidley AM, Love BL, Yeager C, McMichael B, Bookstaver PB. Longterm pharmacotherapy considerations in the bariatric surgery patient. Am J Health Syst Pharm 2016 Aug 15;73(16):1230e42. https://doi.org/10.2146/ ajhp151062. Epub 2016 Jun 28, PMID: 27354038. [27] Chang RK, Raw A, Lionberger R, Yu L. Generic development of topical dermatologic products, Part II: quality by design for topical semisolid products. AAPS J 2013;15(3):674e83. [28] Radha GV, Rani TS, Sarvani B. A review on proniosomal drug delivery system for targeted drug action. J Basic Clin Pharm 2013;4(2):42e8. [29] Walve JR, Rane BR, Gujrathi NA. Proniosomes: a surrogate Carrier for improved transdermal drug delivery system. Int J Res Ayurveda Pharm 2011;2:743e50.
Please cite this article in press as: Bubshait DA, et al., Topical vitamin D3: A randomized controlled trial (RCT), Clinical Nutrition ESPEN (2018), https://doi.org/10.1016/j.clnesp.2018.05.009
Contents lists available at ScienceDirect
Clinical Nutrition ESPEN journal homepage: http://www.clinicalnutritionespen.com
Randomized Controlled Trial
Topical vitamin D3: A randomized controlled trial (RCT) Dalal A. Bubshait a, b, *, Dakheel A. Al-Dakheel a, b, Fawaz M. Alanii a, b a b
Department of Orthopaedic Surgery, College of Medicine, Imam AbdulRahman Bin Faisal University, Dammam King Fahd Hospital of the University, Al Khobar, Saudi Arabia
a r t i c l e i n f o
s u m m a r y
Article history: Received 26 February 2018 Accepted 22 May 2018
Objective: The intent of this study was to test the effect of Top-D, a topical Vitamin D preparation, in delivering vitamin D. Methods: Five hundred and fifty healthy patients, with vitamin D insufficiency and deficiency were recruited after written informed consent. Demographic data was recorded, adequate history and clinical examination was done to rule out any metabolic diseases. Complete blood picture, serum calcium, phosphorous, Parathormone and 25 Hydroxy-vitamin D3 (25OHD) was carried out before enrollment of the patients. Patients were divided randomly into two groups 350 in study group and 200 in the control group. Patients in the study group were given Top-D (Vitamin D3 gel made from proniosomal technology) to apply daily on the skin. Top-D 1 g contained 5000 IU of vitamin D3. The control group was given 1 g of Aloe vera gel to be applied every day. The two groups had no knowledge to which group they belong. After 4 months serum 25OHD was tested again. Results: Three hundred and forty five patients in study group and 192 in control group completed the study. The mean age of the patients in the both the groups was 42 years (18e80 years). The pretreatment 25OHD level in the study group was 11.03 ± 4.57 (2e12) ng/l compared to the control group 10.36 ± 4.09 (2e21) and post treatment the levels were 37.17 ± 6.04 (12e54) ng/ml and 10.51 ± 3.5 (2e19) ng/ml (p < 0.001). Conclusion: The results of this study indicate that transdermal route of vitamin D is potentially, safe and can give desired results to raise the vitamin D levels. This route is an alternate route for supplementation of vitamin D which should be utilized. © 2018 The Authors. Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).
Keywords: Vitamin D3 Topical use Supplementation deficiency Insufficiency
1. Introduction Vitamin D (VD) is one of the fat soluble vitamin which is important to maintain bone health and in prevention of rickets or osteomalacia in the adults. In majority of patients the Vitamin D deficiency or insufficiency occurs due to lack of sun exposure or due nutritional causes. Initial studies in 1980 showed that low level of vitamin D was common among Saudi Arabian population. Sedrani et al. (1983, 1984) [1,2] has shown that vitamin d deficiency existed irrespective of the season due to low exposure to the sunlight. Recent studies of Al-Turki et al. [3], Sadat-Ali et al. [4] found that about 60 percent of men and women in over 50 years of age had vitamin D deficiency but some studies put the deficiency of vitamin
* Corresponding author. King Fahd Hospital of the University, PO BOX 2208, Al Khobar, 31952, Saudi Arabia. E-mail address: [email protected] (D.A. Bubshait).
D to be 95e100% [5,6]. Added to this vitamin D Deficiency persisted even after prescription of vitamin D. One of the reasons that patients did not take medications as they were taking large number of oral medications daily [7 9]. It was reported that many of the oral medications prescribed are taken [10] and it was estimated for noncompliance of oral medications range between 62 and 84 percent [11,12]. hence we believe that in the young and elderly oral route can be avoided if topical route is available. The approval by the US FDA scopolamine as transdermal patch 40 years ago, the number of topical drug delivery increased [13 19]. Vitamin D is available in the form of tablets, drops and injection form and the compliance for oral VD and calcium was less than 60% [20 23]. Segal et al. (2009) [20] found that by end of 3 months, 23.8% of patients were taking properly and 26.2% more were partially compliant. It is our belief that if topical Vitamin D is available, the compliance might increase. This prospective RCT study was done to assess the outcome of topical delivery of VD.
https://doi.org/10.1016/j.clnesp.2018.05.009 2405-4577/© 2018 The Authors. Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism. This is an open access article under the CC BYNC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Bubshait DA, et al., Topical vitamin D3: A randomized controlled trial (RCT), Clinical Nutrition ESPEN (2018), https://doi.org/10.1016/j.clnesp.2018.05.009
2
D.A. Bubshait et al. / Clinical Nutrition ESPEN xxx (2018) 1e4 Table 1 Patients data. Parameter
Study Group
Control Group
Age (Years) Males Females Vitamin D level Pre Treatment (ng/mL) Vitamin D level Post Treatment (ng/mL)
42.59 ± 15.74 (18e80) 65 280 12.03 ± 4.57 (2e12) 37.17 ± 6.04 (12e54)
41.6 ± 16.6 (18e80) 55 137 10.36 ± 4.09 (2e21) 10.51 ± 3.5 (2e19)
2. Patients and methods
3. Results
The study was approved by the IRB of Imam AbdulRahman Bin Faisal University and funded by the Deanship of Scientific Research, Imam AbdulRahman Bin Faisal University, Dammam Saudi Arabia. An informed written consent was obtained from 550 healthy patients, with vitamin D deficiency and vitamin D insufficiency. Patients demographic data was collected. Complete history, thorough clinical examination was done to rule out any metabolic diseases. Blood was collected for complete blood picture, serum calcium, phosphorous, alkaline phosphatase, Parathormone and 25 Hydroxy-vitamin 3 (25OHD) levels. 25OHD3 was measured in King Fahd Hospital of the University, Alkhobar by chemiluminescence immunoassay (CLIA). A vitamin D3 level of 30 ng/mL was accepted as normal, 21e29 ng/mL as insufficiency and 20 ng/mL as deficiency. The patients were randomized into two groups of 350 in study arm and 200 in control arm. Participants were instructed not to change their dietary habits and increase sunlight exposure. Patients in the study group were given Top-D (Vitamin D3 gel made from proniosomal technology) to apply daily on the skin. Top-D 1 g contained 5000 IU of vitamin D3. The control group was given 1 g of Aloe vera gel to be applied every day. The two groups had no knowledge to which group they belong. After 4 months serum 25OHD was tested again. The data was analyzed using SPSS Inc version 19. The Study was monitored by the Monitoring Office for Research and Research Ethics (MORRE) of the Imam AbdulRahman Bin Faisal University, Dammam, Saudi Arabia. The study was registered with www.clinicaltrials.gov. (ClinicalTrials.gov Identifier: NCT02735200).
Three hundred and forty five patients in study group and 192 in control group completed the study. The mean age of the patients in the study group was 42.59 ± 15.74 (18e80) years and 41.6 ± 16.6 (18e80) years in control group. In the study group there were 65 males and 280 females, whereas in control group males were 55 and 137 females (Table 1). The pretreatment 25OH D3 level in the study group was 11.03 ± 4.57 (2e12) ng/mL compared to control group patients 10.36 ± 4.09 (2e21) (p < 0.9) and post treatment levels were 37.17 ± 6.04 (12e54) ng/mL and 10.51 ± 3.5 (2e19) ng/ mL (p < 0.001) (Fig. 1 and Fig. 2). In the study group 36 (10.28%) patients there was failure of vitaminD3 levels to reach above normal level. The level improved from 11.8 ± 4.86 to 20.78 ± 6.15 ng/mL (p < 0.001) (Fig. 3). In the study group 11 patients complained of initial irritation but decided to continue to be in the study. In the control group 7 patients had itching which subsided with time (Aloe-Vera). 4. Discussion The regular use of topical vitamin D3 (TOP-D) was effective in raising vitaminD3 levels within four months above the threshold of 30 ng/mL which was considered as normal levels in this study. The findings of this study is in line with results of the initial reported study [23]. Our study is the first clinical study of level II evidence which involved 345 patients. The justifications of developing a topical delivery of vitamin D are three-fold. The vitamin D deficiency and insufficiency is World wide, even in areas where sunlight is available all the year around and the benefits of vitamin
Fig. 1. Test group.
Please cite this article in press as: Bubshait DA, et al., Topical vitamin D3: A randomized controlled trial (RCT), Clinical Nutrition ESPEN (2018), https://doi.org/10.1016/j.clnesp.2018.05.009
D.A. Bubshait et al. / Clinical Nutrition ESPEN xxx (2018) 1e4
3
Fig. 2. Test group.
Fig. 3. Failure of treatment.
D has made people to go for supplements which are mainly of oral use. The low compliance of oral medications in general are well known and added to the absorption issues of oral vitamin D when improperly taken. The low absorption of vitamin D3 supplementation related to the type and quantity of food is incompletely understood. Raimundo et al. (2011) [24] recently reported the absorption was much better when supplementation was given with a high-fat meal. Patients are not given advice by the manufactures or physicians recommending vitamin D supplementation when to take. Secondly a topical delivery of vitamin D will be ideal for patients with chronic metabolic syndrome and with inflammatory bowel disease as their absorption is unpredictable leaving them with the side effects of hypovitaminosis D [25]. Lastly we believe that there is need of alternate route of vitamin D supplementation in patients post weight reducing surgeries in which there is an altered absorption of vitamin D [26]. Transdermal route for medications have been utilized since 1979 and at present many drugs from steroids to anti-inflammatory
and antibiotics are in routine use [27]. The development of proniosomal and nanotechnology revolutionized drug delivery systems particularly proniosomes due to ease in manufacturing, storage, absorption through the skin [28,29]. The size of the skin pores are approximately the diameter of 50 microns, whereas the average particle size of proniosomal Top-D gel is 3.84 ± 0.35 mm, hence the absorption of vitamin D3 through the pores was without difficulty. Even though ours was a RCT involving good number of patients, we did have a limitation of not performing the absorption studies, which could have strengthened the study robustly. We conclude that the topical delivery of vitamin D3 is achievable and can safely be used in patients particularly those oral absorption in doubt. Conflict of interest None declared.
Please cite this article in press as: Bubshait DA, et al., Topical vitamin D3: A randomized controlled trial (RCT), Clinical Nutrition ESPEN (2018), https://doi.org/10.1016/j.clnesp.2018.05.009
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D.A. Bubshait et al. / Clinical Nutrition ESPEN xxx (2018) 1e4
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Please cite this article in press as: Bubshait DA, et al., Topical vitamin D3: A randomized controlled trial (RCT), Clinical Nutrition ESPEN (2018), https://doi.org/10.1016/j.clnesp.2018.05.009