“Light equals Vitamin D”
~Alfred Fabion Hess
Over the last decade Vitamin D has become the magic elixir that is considered to help or prevent large numbers of health problems of older persons. Besides its effects on bone, vitamin D has been considered to be integral in the cause of immune dysfunction, falls, muscle weakness, cancer, cardiovascular disease, cognitive dysfunction, lung disease, stroke, paraplegia, benign paroxysmal positional vertigo; multiple sclerosis and depression (1-14). Frailty is a major cause of poor outcomes in older individuals (15-22) and has been associated with low levels of 25 (OH) Vitamin D (23-26). These claims are based predominantly on epidemiological studies. 25(OH) vitamin D is formed in the skin from the effect of ultraviolet light i.e., SUNLIGHT. All the diseases purported to be associated with Vitamin D deficiency are also associated with a decreased likelihood of the person going outdoors and thus being exposed to sunlight! (Figure 1). Similarly, while 25(OH) Vitamin D decreases with aging (27), aging is associated with a decreased exposure to sunlight.
Osteomalacia (rickets in children) is the one clear condition due to vitamin D deficiency. These children get weak, painful, deformed long bones due to impaired mineralization of bone. In adults with limited exposure to sunlight and a diet poor in vitamin D, osteomalacia can present with bone pain and muscle weakness along with low calcium and phosphate and elevated alkaline phosphate and parathormone. In adults, this occurs in persons with limited sun exposure and low intake of fish, meat and eggs. An example is adults with cancer and total parenteral nutrition without adequate vitamin D supplementation.
A major role of vitamin D is to enhance the absorption of calcium from the gastrointestinal tract. Low calcium absorption leads to failure to adequately suppress PTH. Elevated PTH causes calcium to be released from the bone. This results in osteoporosis. Utilizing PTH measurement the Institute of Medicine found that normal 25(OH) vitamin D levels should be between 20–25 ng/ml in Caucasian individuals (28).
Vitamin D, like most hormones, is bound to a carrier hormone (vitamin D binding protein – DBP) and it is the free hormone level that is predominantly available to cells (29). Like testosterone, a proportion of vitamin D is also bound to albumin. There are 3 major genetic variants of DBP. The GC*IF allele has a higher frequency is sub-Saharan Africans whereas GC*IS and GC*2 alleles have a higher frequency in pale skin individuals (30). These findings suggest that to measure vitamin D deficiency, a measurement of bioavailable vitamin D (free and albumin bound) is essential. If this is not available, a combination of PTH levels, alkaline phosphatase and calcium levels should be utilized to determine vitamin D deficiency.
Powe et al (31) reported that African Americans have significantly lower 25(OH) vitamin D levels compared to white Americans. They also had lower levels of VDP. In both groups, bioavailable vitamin D was more predictive of PTH concentrations, than total 25(OH) vitamin D levels.
McKee et al (32) found that in African-Americans while a 25(OH) D level of >20ng/ml (>50 nmol/L) were predictive of normal PTH levels, total 25(OH)D levels of <8ng/ml (<20nmol/L) was the cut-off for low bone mineral density. Merchant et al (33) examining a multi-ethnic group in Singapore found that over 50% of Malays and Indians would be considered vitamin D deficient when based on normal levels of 25(OH) D for Caucasians. Only 18.2% of Chinese were deficient. Chinese had the lowest DBP levels with Indians the highest. At present it is clear that there are major problems for the assays measuring 25(OH) vitamin D DBPs and free or bioavailable vitamin D (34,35).
Even when we focus on bone mineral density, hip fractures and falls, a major meta-analysis found that vitamin D supplementation was ineffective (36). Others have suggested that positive effects only occurred in those with the lowest levels of vitamin D (37,38).
So, what is the prudent clinician to conclude from the literature on vitamin D? Firstly, it is clear that the beneficial effects of vitamin D have been greatly oversold. Secondly, measurements of 25(OH) vitamin D are problematic and need to be adjusted for both ethnicity and bioavailability. Thirdly, in persons with low levels of 25(OH) vitamin D (<20ng/ml; 50nmol/L) replacement with low doses of vitamin D (800 to 1000 IU/daily) may be appropriate. There is no evidence for higher doses and a suggestion they may do harm (39). Fourthly, in persons who are ill, malnourished and have very limited sunlight exposure vitamin D replacement might be reasonable, but the supportive data is lacking. Fifthly, new interventional studies on vitamin D replacement concentrating on persons who are deficient are urgently needed. Finally, in an era of precision medicine (40,41) it is essential that attempts are made to determine which individuals will benefit from vitamin D replacement.
This editorial is deliberately provocative and hopefully will stimulate health professionals to re-evaluate the proposition that vitamin D is an emperor who is truly nude or more likely just not very well dressed!
Disclosures: The authors declare there are no conflicts.
References
Bouillon R, Carmeliet G. Vitamin D insufficiency: Definition, diagnosis and management. Best Practice & Research Clinical Endocrinology & Metabolism 2018;32:669–684.
Ji W, Zhou H, Wang S, Cheng L, Fang Y. Low serum levels of 25-hydroxyvitamin D are associated with stroke recurrence and poor functional outcomes in patients with ischemic stroke. J Nutr Health Aging 2017;21:892–896.
Qiu H, Wang M, Mi D, et al. Vitamin D status and the risk of recurrent stroke and mortality in ischemic stroke patients; Data from a 24-month follow-up study in China. J Nutr Health Aging 2017;21:766–771.
Morley JE. Are low levels of 25(OH) vitamin D and testosterone clinically relevant in men with paraplegia? J Spinal Cord Med. 2016;39:253–254.
Morley JE. Dementia: Does vitamin D modulate cognition? Nat Rev Neurol 2014;10:613–614.
Morley JE. Vitamin D redux. J Am Med Dir Assoc 2009;10:591–592.
Morley JE. Should all long-term care residents receive vitamin D? J Am Med Dir Assoc 2007;8:69–70.
Wimalawansa SJ. Non-musculoskeletal benefits of vitamin D. J Steroid Biochem Mol Biol 2018;175:60–81.
AlGarni MA, Mirza AA, Althobaiti AA, et al. Association of benign paroxysmal positional vertigo with vitamin D deficiency: A systematic review and meta-analysis. Eur Arch Otorhinolaryngol 2018;275:2705–2711.
Vellas B, Morley JE. Editorial: Geriatrics in the 21st Century. J Nutr Health Aging 2018;22:186–190.
Wang C, Zeng Z, Wang B, Guo S. Lower 25-Hydroxyvitamin D is associated with higher relapse risk in patients with relapsing-remitting multiple sclerosis. J Nutr Health Aging 2018;22:38–43.
Vidgren M, Virtanen JK, Tolmunen T, et al. Serum concentrations of 25-hydroxyvitamin D and depression in a general middle-aged to elderly population in Finland. J Nutr Health Aging 2018;22:159–164.
Goodwill AM, Szoeke C. A systematic review and meta-analysis of the effect of low vitamin D on cognition. J Am Geriatr Soc 2017;65:2161–2168.
Duval GT, Pare PY, Gautier J, et al. Vitamin D and the mechanisms, circumstances and consequences of falls in older adults: A case-control study. J Nutr Health Aging 2017;21:1307–1313.
Rodriguez Mañas L, Garcia-Sanchez I, Hendry A, et al. Key messages for a frailty prevention and management policy in Europe from the ADVANTAGE JOINT ACTION consortium. J Nutr Health Aging 2018;22:892–897.
Charbek E, Espiritu JR, Nayak R, Morley JE. Editorial: Frailty, comorbidity and COPD. J Nutr Health Aging 2018;22:876–879.
Calle A, Onder G, Morandi A, et al. Frailty related factors as predictors of functional recovery in geriatric rehabilitation: The sarcopenia and function in aging rehabilitation (SAFAR) multi-centric study. J Nutr Health Aging 2018;22:1099–1106.
Gene Huguet L, Navarro Gonzalez M, Kostov B, et al. Pre Fail 80: Multifactorial intervention to prevent progression of pre-frailty to frailty in the elderly. J Nutr Health Aging 2018;22:1266–1274.
Dent E, Morley JE, Cruz-Jentoft AJ, et al. International clinical practice guidelines for sarcopenia (ICFSR): Screening, diagnosis and management. J Nutr Health Aging 2018;22:1148–1161.
Charbek E, Espiritu JR, Nayak R, Morley JE. Editorial: Frailty, comorbidity, and COPD. J Nutr Health Aging 2018;22:876–879.
Dent E, Lien C, Lim WS, et al. The Asia-Pacific clinical practice guidelines for the management of frailty. J Am Med Dir Assoc 2017;18:564–575.
Morley JE, Vellas B, van Kan GA, et al. Frailty consensus: A call to action. J Am Med Dir Assoc 2013;14:392–397.
Krams T, Cesari M, Guyonnet S, et al. Is the 25-hydroxy-vitamin D serum concentration a good marker of frailty? J Nutr Health Aging 2016;20:1034–1039.
Ju SY, Lee JY, Kim DH. Low 25-hydroxyvitamin D levels and the risk of frailty syndrome: A systematic review and dose-response meta-analysis. BMC Geriatr 2018;18:206. Doi: 10.1186/s12877-018-0904-2.
Vaes AMM, Brouwer-Brolsma EM, Toussaint N, et al. The association between 25hydroxyvitamin D concentration, physical performance and frailty status in older adults. Eur J Nutr 2018; Apr 25. Doi: 0.1007/s00394-018-1634-0.
Buta B, Choudhurty PP, Xue QL, et al. The association of vitamin D deficiency and incident frailty in older women: The role of cardiometabolic diseases. J Am Geriatr Soc 2017;65:619–624.
Perry HM 3rd, Horowitz M, Morley JE, et al. Longitudinal changes in serum 25-hydroxyvitamin D in older people. Metabolism 1999;48:1028–1032.
IOM 2011 Dietary reference intakes for calcium and vitamin D. Washington, DC: The National Academies Press.
Davey RX. Vitamin D-binding protein as it is understood in 2016: Is it a critical key with which to help to solve the calcitriol conundrum? Annals of Clinical Biochemistry 2017;54:99–208.
Constans J, Hazout S, Garruto RM, et al. Population distribution of the human vitamin D binding protein: Anthropological considerations. Am J Phys Anthropol 1985.68:107–122.
Powe CE, Evans MK, Wenger J, et al. Vitamin D-binding protein and vitamin D status of black Americans and white Americans. N Engl J Med 2013;369;1991–2000.
McKee A, Lima Ribeiro SM, Malmstrom TK, et al. Screening for vitamin D deficiency in Black Americans: Comparison of total, free, bioavailable 25 hydroxy vitamin D levels with parathyroid hormone levels and bone mineral density. J Nutr Health Aging 2018;22:1045–1050.
Merchant RA, van Dam RM, Tan LWL, et al. Vitamin D binding protein and vitamin D levels in multi-ethnic population. J Nutr Health Aging 2018;22:2060–1065.
Sempos CT, Heijboer AC, Bikle DD, et al. Vitamin D essays and the definition of hypovitaminosis D: Results from the First International Conference on Controversies in Vitamin D. Br J Clin Pharmacol 2018;84:2194–2207.
Thacher TD and Clarke BL. Vitamin D insufficiency. Mayo Clin Proc 2011;86:50–56.
Bolland MJ, Grey A, Avenell A. Effects of vitamin D supplementation on musculoskeletal health: A systematic review, meta-analysis, and trial sequential analysis. Lancet Diabetes Endocrinol 2018;6:847–858.
Beaudart C, Buckinx F, Rabenda V et al. The effects of vitamin D on skeletal muscle strength, muscle mass, and muscle power: A systematic review and meta-analysis of randomized controlled trials. J Clin Endocrinol Metabol 2014;99:4336–4345.
Gillespie LD, Robertson MC, Gillespie WJ, et al. Interventions for preventing falls in older people living in the community. Cochrane Database Systematic Review 2012:Cd007146.
Zheng YT, Cui QQ, Hong YM, Yao WG. A meta-analysis of high dose, intermittent vitamin D supplementation among older adults. PLoS One. 2015;10(1):e0115850.
Morley JE, Anker SD. Myopenia and precision (P4) medicine. J Cachexia Sarcopenia Muscle 2017;8:857–863.
Morley JE, Vellas B. Patient-centered (P4) medicine and the older person. J Am Med Dir Assoc 2017;18:455–459.