Vitamin D has long been considered a central part of the treatment paradigm for osteoporosis. Initial studies in high-risk populations with widespread vitamin D deficiency found a reduction of both vertebral and non-vertebral fractures. Subsequent studies in the general population have yielded mixed but mostly disappointing results both for skeletal and especially non-skeletal outcomes. Recent sequential trial meta-analyses suggest that future studies are likely to be futile given the overall disappointing result. However, mega-trials are still in progress, and additional results have been released. This narrative review aims to evaluate new literature to determine if there has been any substantial change in the message. In conclusion, there is no longer a strong case for initiating vitamin D alone trials in the general adult population, irrespective of age and gender, for significant health outcomes such as fractures, cardiovascular disease and cancer. New studies should focus on risk groups and take directions from the Heaney criteria for evaluation of threshold nutrients. Indeed, real benefits may still be reaped by directing vitamin D supplementation to persons with proven or likely vitamin D deficiency. Further, the role of dietary calcium as a critical co-nutrient remains controversial and could contribute to the discrepancy between studies in terms of cancer outcomes and possibly falls and fractures.
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Bolland MJ, Grey A, Avenell A (2018) Effects of vitamin D supplementation on musculoskeletal health: a systematic review, meta-analysis, and trial sequential analysis. Lancet Diabetes Endocrinol 6:847–858. https://doi.org/10.1016/S2213-8587(18)30265-1
Zhao JG, Zeng XT, Wang J, Liu L (2017) Association between calcium or Vitamin D supplementation and fracture incidence in community-dwelling older adults a systematic review and meta-analysis. JAMA 318:2466–2482. https://doi.org/10.1001/jama.2017.19344
Bolland MJ, Grey A, Gamble GD, Reid IR (2014) The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. Lancet Diabetes Endocrinol 2:307–320. https://doi.org/10.1016/S2213-8587(13)70212-2
Ross AC, Taylor CL, Yaktine AL, Del Valle HB (2011) Dietary reference intakes for calcium and vitamin D. National Academies Press, Washington, DC
Heaney RP (2014) Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev 72:48–54. https://doi.org/10.1111/nure.12090
Chapuy MC, Arlot ME, Duboeuf F et al (1992) Vitamin D3 and calcium to prevent hip fractures in elderly women. N Engl J Med 327:1637–1642. https://doi.org/10.1056/NEJM199212033272305
Freemantle N, Satram-Hoang S, Tang ET et al (2012) Final results of the DAPS (Denosumab Adherence Preference Satisfaction) study: a 24-month, randomized, crossover comparison with alendronate in postmenopausal women. Osteoporos Int 23:317–326. https://doi.org/10.1007/s00198-011-1780-1
DIPART (Vitamin D Individual Patient Analysis of Randomized Trials) Group (2010) Patient level pooled analysis of 68 500 patients from seven major vitamin D fracture trials in US and Europe. BMJ 340:b5463. https://doi.org/10.1136/bmj.b5463
Gillespie LD, Gillespie WJ, Robertson MC et al (2001) Interventions for preventing falls in elderly people. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD000340
Robbins JA, Aragaki A, Crandall CJ et al (2014) Women’s Health Initiative clinical trials: interaction of calcium and vitamin D with hormone therapy. Menopause 21:116–123. https://doi.org/10.1097/GME.0b013e3182963901
Khaw K-T, Stewart AW, Waayer D et al (2017) Effect of monthly high-dose vitamin D supplementation on falls and non-vertebral fractures: secondary and post hoc outcomes from the randomised, double-blind, placebo-controlled ViDA trial. Lancet Diabetes Endocrinol 5:438–447. https://doi.org/10.1016/S2213-8587(17)30103-1
Bislev LS, Langagergaard Rødbro L, Rolighed L et al (2018) Effects of vitamin D3 supplementation on muscle strength, mass, and physical performance in women with vitamin D insufficiency: a randomized placebo-controlled trial. Calcif Tissue Int 103:483–493. https://doi.org/10.1007/s00223-018-0443-z
Hin H, Tomson J, Newman C et al (2017) Optimum dose of vitamin D for disease prevention in older people: BEST-D trial of vitamin D in primary care. Osteoporos Int 28:841–851. https://doi.org/10.1007/s00198-016-3833-y
Aspray TJ, Chadwick T, Francis RM et al (2019) Randomized controlled trial of vitamin D supplementation in older people to optimize bone health. Am J Clin Nutr 109:207–217. https://doi.org/10.1093/ajcn/nqy280
Schnatz PF, Jiang X, Vila-Wright S et al (2014) Calcium/vitamin D supplementation, serum 25-hydroxyvitamin D concentrations, and cholesterol profiles in the Women’s Health Initiative calcium/vitamin D randomized trial. Menopause 21:823–833. https://doi.org/10.1097/GME.0000000000000188
Sollid ST, Hutchinson MYS, Fuskevag OM et al (2014) No effect of high-dose vitamin D supplementation on glycemic status or cardiovascular risk factors in subjects with prediabetes. Diabetes Care 37:2123–2131. https://doi.org/10.2337/dc14-0218
Schnatz PF, Jiang X, Aragaki AK et al (2017) Effects of calcium, vitamin D, and hormone therapy on cardiovascular disease risk factors in the women’s health initiative: a randomized controlled trial. Obstet Gynecol 129:121–129. https://doi.org/10.1097/AOG.0000000000001774
Lappe J, Watson P, Travers-Gustafson D et al (2017) Effect of vitamin D and calcium supplementation on cancer incidence in older women: a randomized clinical trial. JAMA 317:1234–1243. https://doi.org/10.1001/jama.2017.2115
Manson JE, Cook NR, Lee I-M et al (2019) Vitamin D supplements and prevention of cancer and cardiovascular disease. N Engl J Med 380:33–44. https://doi.org/10.1056/NEJMoa1809944
Tomi-Pekka Tuomainen, Jyrki K Virtanen, Sari Voutilainen (2011) Finnish Vitamin D Trial (FIND). In: clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT01463813. Accessed 17 Aug 2019
Neale RE, Armstrong BK, Baxter C et al (2016) The D-health trial: a randomized trial of vitamin D for prevention of mortality and cancer. Contemp Clin Trials 48:83–90. https://doi.org/10.1016/J.CCT.2016.04.005
Pittas AG, Dawson-Hughes B, Sheehan P et al (2019) Vitamin D supplementation and prevention of type 2 diabetes. N Engl J Med 381:520–530. https://doi.org/10.1056/NEJMoa1900906
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Mr Sami reports no conflicts of interest. Dr. Abrahamsen reports institutional research contracts and personal speakers fees from UCB, institutional research contracts from Novartis, personal speakers fees from Eli Lily and from Amgen, outside the submitted work.
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Sami, A., Abrahamsen, B. The Latest Evidence from Vitamin D Intervention Trials for Skeletal and Non-skeletal Outcomes. Calcif Tissue Int 106, 88–93 (2020). https://doi.org/10.1007/s00223-019-00616-y
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