Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Bolland MJ, Grey A, Gamble GD, Reid IR. The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. Lancet Diabetes Endocrinol 2014; published online Jan 24. http://dx.doi.org/10.1016/s2213-8587(13)70212-2.
Appendix: Figure 1: Flow of trials Pubmed search (n=463) Trial-level meta-analysis (n=17) -MI/Stroke (n=4) -Cancer (n=3) -Fracture (n=4) -Mortality (n=6) Reports on vitamin D (n=3) RCTs retrieved -56 reports of 52 trials 12 excluded (see Table 1) RCTs eligible for inclusion -44 reports of 40 trials Page 1 of 4
Table1: Trials excluded from analyses and reasons for exclusion Trial Brohult 1973 1 Grove 1981 2 Larsen 2004 3 Campbell 2005 4 Sato 2005 5 Daly 2006 6 Law 2006 7 Moschonis 2006 8 Schleithoff 2006 9 Berggren 2008 10 Wejse 2009 11 Witham 2010 12 Reason for exclusion Population studied: rheumatoid arthritis Other co-intervention: fluoride plus calcium/vitamin D versus placebo. Cluster randomised controlled trial Other co-intervention: exercise plus vitamin D versus home safety programme versus social visits versus exercise plus vitamin D plus home safety programme Data inconsistencies- awaiting clarification from authors Agent: fortified dairy products Cluster randomised controlled trial Agent: fortified dairy products Population studied: congestive heart failure Other co-intervention: falls prevention programme plus calcium/vitamin D versus controls Population studied: tuberculosis Population studied: congestive heart failure References: 1. Brohult J, Jonson B. Effects of large doses of calciferol on patients with rheumatoid arthritis. A doubleblind clinical trial. Scand J Rheumatol 1973; 2:173-6. 2. Grove O, Halver B. Relief of osteoporotic backache with fluoride, calcium, and calciferol. Acta Med Scand 1981; 209:469-71. 3. Larsen ER, Mosekilde L, Foldspang A. Vitamin D and calcium supplementation prevents osteoporotic fractures in elderly community dwelling residents: a pragmatic population-based 3-year intervention study. J Bone Miner Res 2004; 19:370-8. 4. Campbell AJ, Robertson MC, La Grow SJ, Kerse NM, Sanderson GF, Jacobs RJ, et al. Randomised controlled trial of prevention of falls in people aged > or =75 with severe visual impairment: the VIP trial. BMJ 2005; 331:817. 5. Sato Y, Iwamoto J, Kanoko T, Satoh K. Low-dose vitamin D prevents muscular atrophy and reduces falls and hip fractures in women after stroke: a randomized controlled trial. Cerebrovasc Dis 2005; 20:187-92. 6. Daly RM, Brown M, Bass S, Kukuljan S, Nowson C. Calcium- and vitamin D3-fortified milk reduces bone loss at clinically relevant skeletal sites in older men: a 2-year randomized controlled trial. J Bone Miner Res 2006; 21:397-405. 7. Law M, Withers H, Morris J, Anderson F. Vitamin D supplementation and the prevention of fractures and falls: results of a randomised trial in elderly people in residential accommodation. Age Ageing 2006; 35:482-6. 8. Moschonis G, Manios Y. Skeletal site-dependent response of bone mineral density and quantitative ultrasound parameters following a 12-month dietary intervention using dairy products fortified with calcium and vitamin D: the Postmenopausal Health Study. Br J Nutr 2006; 96:1140-8. 9. Schleithoff SS, Zittermann A, Tenderich G, Berthold HK, Stehle P, Koerfer R. Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial. Am J Clin Nutr 2006; 83:754-9. 10. Berggren M, Stenvall M, Olofsson B, Gustafson Y. Evaluation of a fall-prevention program in older people after femoral neck fracture: a one-year follow-up. Osteoporos Int 2008; 19:801-9. 11. Wejse C, Gomes VF, Rabna P, Gustafson P, Aaby P, Lisse IM, et al. Vitamin D as supplementary treatment for tuberculosis: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med 2009; 179:843-50. 12. Witham MD, Crighton LJ, Gillespie ND, Struthers AD, McMurdo ME. The effects of vitamin D supplementation on physical function and quality of life in older patients with heart failure: a randomized controlled trial. Circ Heart Fail 2010; 3:195-201. Page 2 of 4
Table 2: Subgroup analyses of traditional meta-analysis by baseline and achieved 25OHD levels, and by duration of trial. Baseline 25OHD (nmol/l) Baseline/Achieved 25OHD (nmol/l) Duration of trial <50 50 Missing <50/<50 <50/ 50 50/ 50 Missing 2 years >2 years Myocardial infarction/ischaemic heart disease Studies 5 1 3-5 1 3 3 6 Participants (N) 44,324 892 3471-44,324 892 3471 821 47,866 RR (95% CI) 4 (0.92-1.17) 0 (0.25-8.93) 1.30 (0.67-2.52) - 4 (0.92-1.17) 0 (0.25-8.93) 1.30 (0.67-2.52) 1.90 (0.77-4.71) 1 (0.92-1.12) P (interaction) 0.74 0.74 0.17 Stroke/Cerebrovascular disease Studies 4 1 3-4 1 3 3 5 Participants (N) 42,068 892 3471-42,068 892 3471 821 45,610 RR (95% CI) 0 (0.88-1.13) 1.20 (0.37-3.9) 5 (0.82-1.35) - 0 (0.88-1.13) 1.20 (0.37-3.9) 5 (0.82-1.35) 1.10 (6-2.17) 0 (0.90-1.13) P (interaction) 0.89 0.89 0.80 Cancer Studies 4 1 2-4 1 2 1 6 Participants (N) 44,132 892 3144-44,132 892 3144 302 47,865 RR (95% CI) 0.98 (0.92-4) 0.76 (0.38-5) 0.88 (0.40-1.93) - 0.98 (0.92-4) 0.76 (0.38-5) 0.88 (0.40-1.93) 0.20 (2-1.69) 0.99 (0.93-5) P (interaction) 0.76 0.76 0.14 Total fracture Studies 12 4 6 2 10 4 6 9 13 Participants (N) 55,640 10,194 10,663 353 55,287 10,194 10,663 3520 76,497 RR (95% CI) 0.97 (0.90-6) 0.75 (0.43-1.31) 0.87 (0.77-0.98) 0.38 (0.14-5) 0.98 (0.91-6) 0.75 (0.43-1.31) 0.87 (0.77-0.98) 0.85 (0.70-4) 0.96 (0.89-4) P (interaction) 0.24 0.10 0.28 Hip fracture- Vitamin D Studies 7 1 4 2 5 1 4 4 8 Participants (N) 11,670 9440 6724 278 11,392 9440 6724 1544 26,290 RR (95% CI) 9 (0.91-1.32) 0 (2-2.19) 1 (0.80-1.28) 0.44 (7-2.93) 1.10 (0.92-1.33) 0 (2-2.19) 1 (0.80-1.28) 5 (0.73-3) 1.12 (0.97-1.30) P (interaction) 0.23 0.28 0.77 Hip fracture- calcium/vitamin D Studies 6 1 2 1 5 1 2 2 7 Participants (N) 46,317 389 3384 112 46,205 389 3384 695 49,395 RR (95% CI) 0.84 (0.74-0.97) 0.36 (2-8.79) 0.73 (0.33-1.63) 0.49 (3-7.70) 0.85 (0.72-0) 0.36 (2-8.79) 0.73 (0.33-1.63) 0.64 (0.37-8) 0.85 (0.75-0.98) P (interaction) 0.82 0.91 0.29 Mortality Studies 22 8 8 2 20 8 8 23 15 Participants (N) 57,843 12,180 11,150 355 57,488 12,180 11,150 9958 71,215 RR (95% CI) 0.93 (0.88-0.99) 0.98 (0.85-1.13) 0.98 (0.93-4) 1.37 (0.80-2.35) 0.93 (0.88-0.98) 0.98 (0.85-1.13) 0.98 (0.93-4) 0.96 (0.88-6) 0.96 (0.92-0) P (interaction) 0.41 0.29 0.96 Abbreviations: 25OHD- 25- hydroxyvitamin D; RR- relative risk; CI confidence interval Page 3 of 4
Figure 2: Funnel Plots of Traditional Meta-analyses Funnel Plot of by Myocardial infarction P=6 Funnel Plot of by Total fracture P=2 - - - - - - - - Funnel Plot of by Stroke P=7 Funnel Plot of by Vitamin D Hip fracture P= - - - - - - - - Funnel Plot of by Cancer P=5 Funnel Plot of by Vitamin D/Calcium Hip fracture P= - - - - - - - - Funnel Plot of by Mortality P=0.3 - - - - P-values are for Egger s test. Page 4 of 4