- Email: [email protected]
Vitamin D and the endocrinology of ageing
Accepted Manuscript Vitamin D and the endocrinology of aging Leon Flicker, Director PII:
S2451-9650(18)30031-0
DOI:
https://doi.org/10.1016/j.coemr.2018.12.001
Reference:
COEMR 48
To appear in:
Current Opinion in Endocrine and Metabolic Research
Received Date: 24 November 2018 Accepted Date: 10 December 2018
Please cite this article as: Flicker L, Vitamin D and the endocrinology of aging, Current Opinion in Endocrine and Metabolic Research, https://doi.org/10.1016/j.coemr.2018.12.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Vitamin D and the endocrinology of aging
Leon Flicker
Geriatrician Royal Perth Hospital
Word Count: Abstract – 129 Body of paper – 2055
Address for Correspondence Professor Leon Flicker
M AN U
References: 32
Royal Perth Hospital, Box X2213 GPO
AUSTRALIA
TE D
Perth. WA. 6001
Telephone No. 618 9224 0377
EP
Facsimile No. 618 9224 0364
AC C
Email: [email protected]
SC
Medicine, Medical School, University of Western Australia
RI PT
Director, Western Australian Centre for Health and Ageing, Professor of Geriatric
ACCEPTED MANUSCRIPT Abstract Vitamin D is an important prohormone largely derived from sunlight exposure on the skin. In many older people vitamin D levels have been found to be insufficient or frankly deficient. Alterations in body composition associated with
RI PT
ageing, such as decreased muscle mass and increased adipose tissue, may also
decrease vitamin D levels. Low vitamin D levels are associated with an increased risk of falls and fractures, and the conditions of frailty and sarcopenia, but
SC
confounding with decreased outdoor exposure from a large range of concomitant diseases partly explains these findings. The benefits of vitamin D
M AN U
supplementation found in randomized trials have largely been confined to frail and disabled older people. There is some evidence that bolus vitamin D supplements that achieve supra-physiological levels may increase the risk of
TE D
falls.
AC C
EP
Keywords: Vitamin D, ageing, falls, frailty, sarcopenia
ACCEPTED MANUSCRIPT Introduction Vitamin D was first identified because of its involvement in the bone deforming disease of rickets in children. Early in the twentieth century, even before the discovery of vitamin D, it was found that sunlight could be used to cure children
RI PT
suffering with rickets [1]. Since then, the formation and activation of this hormone has been elucidated. Vitamin D3, (D3) is synthesized from the
provitamin, 7-dehydrocholesterol, by exposure to ultraviolet B (UVB) light in the
SC
skin [2]. Thus, the term vitamin D is a misnomer in that the vast majority of humans do not obtain this substance from the diet but from endogenous
M AN U
production. Since its discovery there have been many other hypothesized roles for vitamin D in diseases of humans besides its known role in the calcification of bone matrix. The importance of vitamin D in these other conditions, many of
TE D
which are age-dependent, is at this stage largely inconclusive.
The study of the role of vitamin D in human diseases is confounded by the known
EP
mechanism of the formation of D3. Production of D3 is dependent on sunlight exposure. Thus any health condition that decreases sunlight exposure through
AC C
limited exercise tolerance, e.g. cancer, or decreased predilection to spending time outdoors, e.g. depression, will decrease production of D3. Nearly all available cholecalciferol is converted in the liver to the relatively inert 25hydroxyvitamin D (25(OH)D). This is the major body store of vitamin D and its half-life is probably at least three months [3]. Besides genetic factors like the vitamin D receptor gene polymorphisms [3], other factors may be important. There is some evidence that 25(OH)D may be trapped by adipose tissue, lowering the levels of 25(OH)D whereas skeletal muscle may be a useful storage
ACCEPTED MANUSCRIPT mechanism for 25(OH)D[4]. These recent findings highlight how sensitive levels of 25(OH)D are to the effects of lifestyle and disease.
Ageing in humans is accompanied by physiological changes and an increased risk
RI PT
of some diseases. Some syndromes have been characterized as being heavily age dependent, including falls, frailty and sarcopenia. These syndromes almost certainly are the product of physiological changes interacting with age-
SC
dependent diseases. In addition osteoporotic fractures are also extremely
commonplace with ageing, the most serious of which, hip fractures, double in
M AN U
incidence for every 5 years past the age of 70 years[5]. Vitamin D has been thought to be linked to all these age related syndromes and it may be the interaction between these ageing syndromes and the known skeletal effects of
TE D
vitamin D that may result in the putative benefits of vitamin D supplementation.
Vitamin D and Fractures
EP
There is no clear association between vitamin D levels and ageing from evidence provided by the known four longitudinal studies [6]. However in disabled older
AC C
people, when ageing is confounded by the effects of disease and decreased sun exposure there is an increased prevalence of vitamin D deficiency (less than 25nmol/l) and insufficiency (less than 50 nmol/l). In one study of frail older people who were entering residential care the prevalence of vitamin D deficiency was 41% and another 45% had insufficient levels[7]. Insufficiency and deficiency of vitamin D results in elevated serum parathyroid levels [8] that is thought to increase the loss of bone mass over time. As older people with vitamin D insufficiency are likely to have other conditions that may make them prone to
ACCEPTED MANUSCRIPT fractures, randomized trials of D supplementation are required. Unfortunately there are many trials with conflicting results. Relying on published data, the Cochrane review examined 53 trials with a total of 91,791 participants [9]. The authors concluded that vitamin D plus calcium results in a small reduction in hip
RI PT
fracture risk (nine trials, 49,853 participants; relative risk (RR) 0.84, (95%
confidence interval (CI) 0.74 to 0.96). Data comparing vitamin D alone with
placebo or no treatment showed no statistically significant effect on hip fracture
SC
(11 trials, 27,693 participants, RR 1.12, 95% CI 0.98 to 1.29). It is important to highlight one negative study included in this meta-analysis, the Vital D study
M AN U
[10]. This study used as the intervention single annual dose of 500 000 IU of cholecalciferol administered orally to older women over the age of 70 years living in the community. Overall there was in increase in fractures RR 1.26 95% CI, 1.00 to 1.59 and the incidence rate ratio for falls was 1.15; 95% CI, 1.02 to
TE D
1.30. The increased rate of falls was largely confined to a period of three months after administration of vitamin D supplements. An individual patient data meta-
EP
analysis has also been performed and was able to obtain data on 31,022 persons, mean age 76 years, mostly women [11]. In this meta-analysis, for those
AC C
participants taking relatively higher doses of vitamin D (median 800 IU daily), a reduction in hip fracture RR, 0.70; 95% CI, 0.58 to 0.86 and any nonvertebral fracture RR 0.86; 95% CI, 0.76 to 0.96 was found.
Vitamin D and Falls Falls are the quintessential syndrome associated with ageing. Falls represent the product of multiple diseases and risk factors interacting with the environment, that includes medications [12]. Balance and neuromuscular control are essential
ACCEPTED MANUSCRIPT to maintain an upright posture and abnormalities increase the risk for falls [13]. It is uncertain whether the vitamin D receptor (VDR) is found in muscle cells [14] but a role for vitamin D in nervous tissue has been supported by the presence of these receptors [15]. Low vitamin D levels have been associated prospectively
RI PT
with an increased risk of falls [16]. However, physical inactivity is associated
with many diseases and risk factors for falls, and this would result in decreased sun exposure and the association. Thus randomized trials are required to both
SC
demonstrate causation and provide an avenue for treatment. There have been many trials of vitamin D supplements with falls as an outcome. There are two
M AN U
overarching Cochrane reviews on falls. One review analyzed intervention studies addressing the issue of falls in people who live in the community [17]. This review included 14 trials with 28,135 participants randomized to vitamin D, either alone or with calcium supplementation. Overall there was no substantial
TE D
effect of vitamin D supplementation, RR 0.96, 95% CI 0.89 to 1.03. There was a reduction in rate of falls and risk of falling in the trials only recruiting
EP
participants with lower vitamin D levels, relative rate ratio (RaR) 0.57, 95% CI 0.37 to 0.89 (260 participants, 2 trials) and RR 0.70, 95% CI 0.56 to 0.87 (804
AC C
participants, 4 trials). On the other hand the review addressing the issues of falls in care facilities and hospitals found substantially different results [18]. In four trials incorporating 4512 participants Vitamin D supplementation reduced the rate of falls, RaR 0.72, 95% CI 0.55 to 0.95; but the risk of falling was not substantially affected RR 0.92, 95% CI 0.76 to 1.12. The conclusion from all these studies is that the effect of vitamin D supplementation for falls is greatest for those individuals who are frail and have low levels of vitamin D. There has been a further recent trial of vitamin D supplementation that has largely confirmed
ACCEPTED MANUSCRIPT previous findings. This study of 5110 healthy volunteers aged 50 to 84 years used a monthly dose of 100,000 IU of cholecaciferol or placebo [19]. Only 30% of participants had an insufficient level of 25 (OH) D at baseline. The Hazard ratio for falls was 0.99 (95% CI 0.92 to 1.07) and for fractures was 1.19 (95% CI 0.94
RI PT
to 1.50). There has been another recent study that has reinforced concerns
raised by the Vital D study [20]. This study enrolled 200 participants aged over 70 years with a previous fall and 58% had insufficient levels of 25(OH)D. The
SC
participants were randomized to one of three groups, oral supplementation on a
M AN U
monthly basis of 1) 24,000 IU D3, or 2) 60,000 IU D3 or 3) 24,000IU D3 plus 300µg of calcifediol. The proportion of fallers and the mean number of falls were higher in the high dose groups compared with those receiving 24,000IU D3 per month. Those people who were vitamin D replete at baseline were most likely to
TE D
fall on the higher dose of 60,000IU D3 per month.
Vitamin D and Frailty
EP
Until recently frailty has been poorly defined with clinicians ascribing the condition to widely different characteristics. It has now been defined as a
AC C
reduced strength and physiologic malfunctioning that increases an individual’s susceptibility to increased dependency, vulnerability, and death [21]. There are three major approaches to defining frailty, 1) a physical phenotype model, popularized by Fried et al [22] or a rapid screen for the phenotype using the FRAIL scale [23], 2) a deficit accumulation model popularized by Rockwood and Mitnitski [24] and 3) a mixed physical and psychosocial model e.g. Edmonton Frailty Scale [25]. Modern guidelines for assessment and management of frailty frequently include recommendations to screen and treat for vitamin D
ACCEPTED MANUSCRIPT insufficiency [26]. This has relied on the evidence that low vitamin D levels are associated with prevalent and incident frailty [27]. In a systematic review of seven prospective observational studies with 17,815 participants, the pooled odds ratio for frailty comparing the lowest versus the highest level of vitamin D
RI PT
was 1.27 95% CI 1.17 to1.38 [28]. The association between hypovitaminosis D
and frailty has been comprehensively reviewed [29]. There are clear associations between low vitamin D levels and muscle weakness and other hallmarks of
SC
frailty. Unfortunately there are no randomized trials demonstrating a reduction
Vitamin D and Sarcopenia
M AN U
or reversal of frailty with vitamin D supplementation.
The World Health Organization recently listed sarcopenia as a disease for the International Statistical Classification of Diseases and Related Health Problems
TE D
10th revision (ICD-10) [30]. Sarcopenia had originally been defined as a condition of low muscle mass associated with ageing but the more recent definitions have
EP
placed greater importance on muscle strength as opposed to mass. The European Working Group on Sarcopenia in Older People have very recently
AC C
revised their recommendations. Sarcopenia is now defined as “a progressive and generalised skeletal muscle disorder that is associated with increased likelihood of adverse outcomes including falls, fractures, physical disability and mortality” [31]. Low muscle strength is thought to be the most important parameter of sarcopenia and the diagnosis is supported by low muscle quantity or quality and low physical performance. This is because evidence has accrued that muscle strength is more predictive of adverse outcomes. The causes of sarcopenia are
ACCEPTED MANUSCRIPT manifold and may be considered as primary, or age related, or secondary due to diseases, inactivity or malnutrition.
Low vitamin D levels have been demonstrated to be associated with low muscle
RI PT
strength and muscle mass, and poor physical performance in many observational studies [29]. Unfortunately there are no trials of vitamin D supplementation used alone with the outcome of sarcopenia. There is one 13 weeks trial of a combined
SC
intervention of 800IU of vitamin D and a leucine enriched protein supplement
[32]. All participants were community dwelling and had sarcopenia diagnosed by
M AN U
poor physical performance and low muscle mass as measured by bio-impedance. The active group improved more on the chair stand test, a test of lower limb muscle strength and gained slightly more muscle mass. Whether the effect was
Conclusions
TE D
due to the vitamin D, the protein supplement or both is unknown.
EP
There is considerable observational evidence that low vitamin D levels are associated with an increased risk of fractures and falls, and the conditions of
AC C
frailty and sarcopenia commonly found in older people. Older people who have multiple diseases with concomitant disability are more likely to have both vitamin D insufficiency and these conditions. The recently discovered observation that low muscle mass and high adipose tissue may further decrease vitamin D levels would suggest that a deleterious cascade may exist between vitamin D levels and frailty and sarcopenia. This would explain the findings from the randomized trials where the beneficial effects of vitamin D supplementation for falls are confined to frail older people with vitamin D insufficiency. There are
ACCEPTED MANUSCRIPT now two studies that have found an increased propensity to fall with high bolus vitamin D supplements underlining the potential risks of achieving nonphysiological levels of vitamin D. As yet it is not clear whether vitamin D supplementation can address the common problems of frailty and sarcopenia,
RI PT
but in those patients with these conditions and found to have vitamin D
insufficiency or deficiency it would be prudent to achieve physiological vitamin D
AC C
EP
TE D
M AN U
SC
levels.
ACCEPTED MANUSCRIPT References [1] DeLuca HF. History of the discovery of vitamin D and its active metabolites Bonekey Rep. 2014; 3: 479. [2] Stein MS, Wark JD. An update on the therapeutic potential of vitamin D
RI PT
analogues Expert Opin Investig Drugs. 2003 May;12(5):825-40.
[3] Datta P, Philipsen PA, Olsen P, Bogh MK, Johansen P, Schmedes AV, et al. The half-life of 25(OH)D after UVB exposure depends on gender and vitamin D
SC
receptor polymorphism but mainly on the start level. Photochem Photobiol Sci. 2017 Jun 14;16(6):985-995
M AN U
*[4]Abboud M, Rybchyn MS, Rizk R, Fraser DR, Mason RS. Sunlight exposure is just one of the factors which influence vitamin D status. Photochem Photobiol Sci. 2017 Mar 16;16(3):302-313.
This paper presents data suggesting that low skeletal mass and high levels of
TE D
adipose tissue can lower vitamin D levels
[5] Bolland MJ, Jackson R, Gamble GD, Grey A. Discrepancies in predicted
EP
fracture risk in elderly people. BMJ. 2013; 346:e8669. [6] de Jongh RT, van Schoor NM, Lips P. Changes in vitamin D endocrinology
AC C
during aging in adults. Mol Cell Endocrinol. 2017 Sep 15;453:144-150 [7] Komar L, Nieves J, Cosman F, Rubin A, Shen V, Lindsay R. Calcium homeostasis of an elderly population upon admission to a nursing home. J Am Geriatr Soc. 1993; 41:1057-64. [8] Lips P, Duong T, Oleksik A, Black D, Cummings S, Cox D, Nickelsen T. A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the multiple outcomes of raloxifene evaluation clinical trial. J Clin Endocrinol Metab. 2001; 86:1212-21
ACCEPTED MANUSCRIPT [9] Avenell A, Mak JCS, O'Connell D. Vitamin D and vitamin D analogues for preventing fractures in post‐menopausal women and older men. Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD000227. DOI: 10.1002/14651858.CD000227.pub4
RI PT
[10] Sanders KM, Stuart AL, Williamson EJ, Simpson JA, Kotowicz MA, Young D, et al. Annual high‐dose oral vitamin D and falls and fractures in older women. A
SC
randomized controlled trial. JAMA 2010; 303:1815‐22.
[11] Bischoff-Ferrari HA, Willett WC, Oray EJ, Lips P, Meunier PJ, Lyons RA, et al.
Engl J Med 2012; 367:40-9
M AN U
A Pooled Analysis of Vitamin D Dose Requirements for Fracture Prevention N
[12] Tinetti ME, Speechley M, Ginter SF. Risk factors for falls among elderly persons living in the community. N Engl J Med. 1988; 319:1701-7
TE D
[13] Lord SR, Ward JA, Williams P, Anstey KJ. Physiological factors associated with falls in older community-dwelling women. J Am Geriatr Soc. 1994; 42:11107
EP
[14] Bouillon R, Marcocci C, Carmeliet G, Bikle D, White JH, Dawson-Hughes B, Lips P, Munns CF, Lazaretti-Castro M, Giustina A, Bilezikian J.
AC C
Skeletal and extra-skeletal actions of vitamin D: Current evidence and outstanding questions. Endocr Rev. 2018 Oct 12. doi: 10.1210/er.2018-00126. [15] Garcion E, Wion-Barbot N, Montero-Menei CN, Berger F, Wion D. New clues about vitamin D functions in the nervous system. Trends Endocrinol Metab. 2002;13:100-5
ACCEPTED MANUSCRIPT [16] Flicker L, Mead K, MacInnis RJ, Nowson C, Scherer S, Stein MS, et al. Serum vitamin D and falls in older women in residential care in Australia. J Am Geriatr Soc. 2003; 51:1533-8 [17] Gillespie LD, Robertson MC, Gillespie WJ, Sherrington C, Gates S, Clemson
RI PT
LM, Lamb SE. Interventions for preventing falls in older people living in the
community. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD007146
SC
*[18] Cameron ID, Dyer SM, Panagoda CE, Murray GR, Hill KD, Cumming RG,
Kerse N. Interventions for preventing falls in older people in care facilities and
CD005465.
M AN U
hospitals. Cochrane Database of Systematic Reviews 2018, Issue 9. Art. No.:
This updated meta-analysis found evidence of reduced falls with treatment using vitamin D supplements
TE D
[19] Khaw KT, Stewart AW, Waayer D, Lawes CMM, Toop L, Camargo CA Jr, Scragg R. Effect of monthly high-dose vitamin D supplementation on falls and
EP
non-vertebral fractures: secondary and post-hoc outcomes from the randomised, double-blind, placebo-controlled ViDA trial. Lancet Diabetes Endocrinol. 2017;
AC C
5:438-447
**[20] Bischoff-Ferrari HA, Dawson-Hughes B, Orav EJ, Staehelin HB, Meyer OW, Theiler R, et al. Monthly High-Dose Vitamin D Treatment for the Prevention of Functional Decline: A Randomized Clinical Trial. JAMA Intern Med. 2016; 176:175-83. This study found an increased rate of falls in those trial participants receiving high doses of vitamin D supplements [21] Morley JE, Vellas B, van Kan GA, et al. Frailty consensus: A call to action. J Am
ACCEPTED MANUSCRIPT Med Dir Assoc 2013;14:392e397. [22] Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: Evidence for a phenotype. J Gerontol A Biol Sci Med Sci 2001;56:M146eM156. [23] Morley JE, Malmstrom TK, Miller DK. A simple frailty questionnaire (FRAIL)
RI PT
predicts outcomes in middle aged African Americans. J Nutr Health Aging 2012;16:601e608
measure of aging. Sci World J 2001;1:323e336.
SC
[24] Mitnitski AB, Mogilner AJ, Rockwood K. Accumulation of deficits as a proxy
[25] Rolfson DB, Majumdar SR, Tsuyuki RT, et al. Validity and reliability of the
M AN U
Edmonton Frail Scale. Age Ageing 2006;35:526e529.
[26] Dent E, Lien C, Lim WS, Wong WC, Wong CH, Ng TP, et al. The Asia-Pacific Clinical Practice Guidelines for the Management of Frailty. J Am Med Dir Assoc. 2017; 18:564-575
TE D
[27] Wong YY, McCaul KA, Yeap BB, Hankey GJ, Flicker L. Low vitamin D status is an independent predictor of increased frailty and all-cause mortality in older
EP
men: The Health in Men Study. J Clin Endocrinol Metab 2013;98:3821e3828. [28] Zhou J, Huang P, Liu P, Hao Q, Chen S, Dong B, Wang J. Association of vitamin
AC C
D deficiency and frailty: A systematic review and meta-analysis. Maturitas 2016; 94:70-76.
[29] Wong YY, Flicker L. Hypovitaminosis D and frailty: epiphenomenon or causal? Maturitas 2015; 82: 328–335. * [30] Anker SD, Morley JE, von Haehling S. Welcome to the ICD-10 code for sarcopenia. J Cachexia Sarcopenia Muscle. 2016; 7:512-514. Sarcopenia is now a listed condition for the ICD-10 classification
ACCEPTED MANUSCRIPT [31] Cruz-Jentoft AJ, Bahat G, Bauer J. Boirie Y, Bruyère O, Cederholm T, et al. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing. 2018 Oct 12. doi: 10.1093/ageing/afy169. [Epub ahead of print] [32] Bauer JM, Verlaan S, Bautmans I, Brandt K, Donini LM, Maggio M, et al.
RI PT
Effects of a vitamin D and leucine-enriched whey protein nutritional supplement on measures of sarcopenia in older adults, the PROVIDE study: a randomized,
AC C
EP
TE D
M AN U
SC
double-blind, placebo-controlled trial. J Am Med Dir Assoc. 2015; 16:740-7.
S2451-9650(18)30031-0
DOI:
https://doi.org/10.1016/j.coemr.2018.12.001
Reference:
COEMR 48
To appear in:
Current Opinion in Endocrine and Metabolic Research
Received Date: 24 November 2018 Accepted Date: 10 December 2018
Please cite this article as: Flicker L, Vitamin D and the endocrinology of aging, Current Opinion in Endocrine and Metabolic Research, https://doi.org/10.1016/j.coemr.2018.12.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Vitamin D and the endocrinology of aging
Leon Flicker
Geriatrician Royal Perth Hospital
Word Count: Abstract – 129 Body of paper – 2055
Address for Correspondence Professor Leon Flicker
M AN U
References: 32
Royal Perth Hospital, Box X2213 GPO
AUSTRALIA
TE D
Perth. WA. 6001
Telephone No. 618 9224 0377
EP
Facsimile No. 618 9224 0364
AC C
Email: [email protected]
SC
Medicine, Medical School, University of Western Australia
RI PT
Director, Western Australian Centre for Health and Ageing, Professor of Geriatric
ACCEPTED MANUSCRIPT Abstract Vitamin D is an important prohormone largely derived from sunlight exposure on the skin. In many older people vitamin D levels have been found to be insufficient or frankly deficient. Alterations in body composition associated with
RI PT
ageing, such as decreased muscle mass and increased adipose tissue, may also
decrease vitamin D levels. Low vitamin D levels are associated with an increased risk of falls and fractures, and the conditions of frailty and sarcopenia, but
SC
confounding with decreased outdoor exposure from a large range of concomitant diseases partly explains these findings. The benefits of vitamin D
M AN U
supplementation found in randomized trials have largely been confined to frail and disabled older people. There is some evidence that bolus vitamin D supplements that achieve supra-physiological levels may increase the risk of
TE D
falls.
AC C
EP
Keywords: Vitamin D, ageing, falls, frailty, sarcopenia
ACCEPTED MANUSCRIPT Introduction Vitamin D was first identified because of its involvement in the bone deforming disease of rickets in children. Early in the twentieth century, even before the discovery of vitamin D, it was found that sunlight could be used to cure children
RI PT
suffering with rickets [1]. Since then, the formation and activation of this hormone has been elucidated. Vitamin D3, (D3) is synthesized from the
provitamin, 7-dehydrocholesterol, by exposure to ultraviolet B (UVB) light in the
SC
skin [2]. Thus, the term vitamin D is a misnomer in that the vast majority of humans do not obtain this substance from the diet but from endogenous
M AN U
production. Since its discovery there have been many other hypothesized roles for vitamin D in diseases of humans besides its known role in the calcification of bone matrix. The importance of vitamin D in these other conditions, many of
TE D
which are age-dependent, is at this stage largely inconclusive.
The study of the role of vitamin D in human diseases is confounded by the known
EP
mechanism of the formation of D3. Production of D3 is dependent on sunlight exposure. Thus any health condition that decreases sunlight exposure through
AC C
limited exercise tolerance, e.g. cancer, or decreased predilection to spending time outdoors, e.g. depression, will decrease production of D3. Nearly all available cholecalciferol is converted in the liver to the relatively inert 25hydroxyvitamin D (25(OH)D). This is the major body store of vitamin D and its half-life is probably at least three months [3]. Besides genetic factors like the vitamin D receptor gene polymorphisms [3], other factors may be important. There is some evidence that 25(OH)D may be trapped by adipose tissue, lowering the levels of 25(OH)D whereas skeletal muscle may be a useful storage
ACCEPTED MANUSCRIPT mechanism for 25(OH)D[4]. These recent findings highlight how sensitive levels of 25(OH)D are to the effects of lifestyle and disease.
Ageing in humans is accompanied by physiological changes and an increased risk
RI PT
of some diseases. Some syndromes have been characterized as being heavily age dependent, including falls, frailty and sarcopenia. These syndromes almost certainly are the product of physiological changes interacting with age-
SC
dependent diseases. In addition osteoporotic fractures are also extremely
commonplace with ageing, the most serious of which, hip fractures, double in
M AN U
incidence for every 5 years past the age of 70 years[5]. Vitamin D has been thought to be linked to all these age related syndromes and it may be the interaction between these ageing syndromes and the known skeletal effects of
TE D
vitamin D that may result in the putative benefits of vitamin D supplementation.
Vitamin D and Fractures
EP
There is no clear association between vitamin D levels and ageing from evidence provided by the known four longitudinal studies [6]. However in disabled older
AC C
people, when ageing is confounded by the effects of disease and decreased sun exposure there is an increased prevalence of vitamin D deficiency (less than 25nmol/l) and insufficiency (less than 50 nmol/l). In one study of frail older people who were entering residential care the prevalence of vitamin D deficiency was 41% and another 45% had insufficient levels[7]. Insufficiency and deficiency of vitamin D results in elevated serum parathyroid levels [8] that is thought to increase the loss of bone mass over time. As older people with vitamin D insufficiency are likely to have other conditions that may make them prone to
ACCEPTED MANUSCRIPT fractures, randomized trials of D supplementation are required. Unfortunately there are many trials with conflicting results. Relying on published data, the Cochrane review examined 53 trials with a total of 91,791 participants [9]. The authors concluded that vitamin D plus calcium results in a small reduction in hip
RI PT
fracture risk (nine trials, 49,853 participants; relative risk (RR) 0.84, (95%
confidence interval (CI) 0.74 to 0.96). Data comparing vitamin D alone with
placebo or no treatment showed no statistically significant effect on hip fracture
SC
(11 trials, 27,693 participants, RR 1.12, 95% CI 0.98 to 1.29). It is important to highlight one negative study included in this meta-analysis, the Vital D study
M AN U
[10]. This study used as the intervention single annual dose of 500 000 IU of cholecalciferol administered orally to older women over the age of 70 years living in the community. Overall there was in increase in fractures RR 1.26 95% CI, 1.00 to 1.59 and the incidence rate ratio for falls was 1.15; 95% CI, 1.02 to
TE D
1.30. The increased rate of falls was largely confined to a period of three months after administration of vitamin D supplements. An individual patient data meta-
EP
analysis has also been performed and was able to obtain data on 31,022 persons, mean age 76 years, mostly women [11]. In this meta-analysis, for those
AC C
participants taking relatively higher doses of vitamin D (median 800 IU daily), a reduction in hip fracture RR, 0.70; 95% CI, 0.58 to 0.86 and any nonvertebral fracture RR 0.86; 95% CI, 0.76 to 0.96 was found.
Vitamin D and Falls Falls are the quintessential syndrome associated with ageing. Falls represent the product of multiple diseases and risk factors interacting with the environment, that includes medications [12]. Balance and neuromuscular control are essential
ACCEPTED MANUSCRIPT to maintain an upright posture and abnormalities increase the risk for falls [13]. It is uncertain whether the vitamin D receptor (VDR) is found in muscle cells [14] but a role for vitamin D in nervous tissue has been supported by the presence of these receptors [15]. Low vitamin D levels have been associated prospectively
RI PT
with an increased risk of falls [16]. However, physical inactivity is associated
with many diseases and risk factors for falls, and this would result in decreased sun exposure and the association. Thus randomized trials are required to both
SC
demonstrate causation and provide an avenue for treatment. There have been many trials of vitamin D supplements with falls as an outcome. There are two
M AN U
overarching Cochrane reviews on falls. One review analyzed intervention studies addressing the issue of falls in people who live in the community [17]. This review included 14 trials with 28,135 participants randomized to vitamin D, either alone or with calcium supplementation. Overall there was no substantial
TE D
effect of vitamin D supplementation, RR 0.96, 95% CI 0.89 to 1.03. There was a reduction in rate of falls and risk of falling in the trials only recruiting
EP
participants with lower vitamin D levels, relative rate ratio (RaR) 0.57, 95% CI 0.37 to 0.89 (260 participants, 2 trials) and RR 0.70, 95% CI 0.56 to 0.87 (804
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participants, 4 trials). On the other hand the review addressing the issues of falls in care facilities and hospitals found substantially different results [18]. In four trials incorporating 4512 participants Vitamin D supplementation reduced the rate of falls, RaR 0.72, 95% CI 0.55 to 0.95; but the risk of falling was not substantially affected RR 0.92, 95% CI 0.76 to 1.12. The conclusion from all these studies is that the effect of vitamin D supplementation for falls is greatest for those individuals who are frail and have low levels of vitamin D. There has been a further recent trial of vitamin D supplementation that has largely confirmed
ACCEPTED MANUSCRIPT previous findings. This study of 5110 healthy volunteers aged 50 to 84 years used a monthly dose of 100,000 IU of cholecaciferol or placebo [19]. Only 30% of participants had an insufficient level of 25 (OH) D at baseline. The Hazard ratio for falls was 0.99 (95% CI 0.92 to 1.07) and for fractures was 1.19 (95% CI 0.94
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to 1.50). There has been another recent study that has reinforced concerns
raised by the Vital D study [20]. This study enrolled 200 participants aged over 70 years with a previous fall and 58% had insufficient levels of 25(OH)D. The
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participants were randomized to one of three groups, oral supplementation on a
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monthly basis of 1) 24,000 IU D3, or 2) 60,000 IU D3 or 3) 24,000IU D3 plus 300µg of calcifediol. The proportion of fallers and the mean number of falls were higher in the high dose groups compared with those receiving 24,000IU D3 per month. Those people who were vitamin D replete at baseline were most likely to
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fall on the higher dose of 60,000IU D3 per month.
Vitamin D and Frailty
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Until recently frailty has been poorly defined with clinicians ascribing the condition to widely different characteristics. It has now been defined as a
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reduced strength and physiologic malfunctioning that increases an individual’s susceptibility to increased dependency, vulnerability, and death [21]. There are three major approaches to defining frailty, 1) a physical phenotype model, popularized by Fried et al [22] or a rapid screen for the phenotype using the FRAIL scale [23], 2) a deficit accumulation model popularized by Rockwood and Mitnitski [24] and 3) a mixed physical and psychosocial model e.g. Edmonton Frailty Scale [25]. Modern guidelines for assessment and management of frailty frequently include recommendations to screen and treat for vitamin D
ACCEPTED MANUSCRIPT insufficiency [26]. This has relied on the evidence that low vitamin D levels are associated with prevalent and incident frailty [27]. In a systematic review of seven prospective observational studies with 17,815 participants, the pooled odds ratio for frailty comparing the lowest versus the highest level of vitamin D
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was 1.27 95% CI 1.17 to1.38 [28]. The association between hypovitaminosis D
and frailty has been comprehensively reviewed [29]. There are clear associations between low vitamin D levels and muscle weakness and other hallmarks of
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frailty. Unfortunately there are no randomized trials demonstrating a reduction
Vitamin D and Sarcopenia
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or reversal of frailty with vitamin D supplementation.
The World Health Organization recently listed sarcopenia as a disease for the International Statistical Classification of Diseases and Related Health Problems
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10th revision (ICD-10) [30]. Sarcopenia had originally been defined as a condition of low muscle mass associated with ageing but the more recent definitions have
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placed greater importance on muscle strength as opposed to mass. The European Working Group on Sarcopenia in Older People have very recently
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revised their recommendations. Sarcopenia is now defined as “a progressive and generalised skeletal muscle disorder that is associated with increased likelihood of adverse outcomes including falls, fractures, physical disability and mortality” [31]. Low muscle strength is thought to be the most important parameter of sarcopenia and the diagnosis is supported by low muscle quantity or quality and low physical performance. This is because evidence has accrued that muscle strength is more predictive of adverse outcomes. The causes of sarcopenia are
ACCEPTED MANUSCRIPT manifold and may be considered as primary, or age related, or secondary due to diseases, inactivity or malnutrition.
Low vitamin D levels have been demonstrated to be associated with low muscle
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strength and muscle mass, and poor physical performance in many observational studies [29]. Unfortunately there are no trials of vitamin D supplementation used alone with the outcome of sarcopenia. There is one 13 weeks trial of a combined
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intervention of 800IU of vitamin D and a leucine enriched protein supplement
[32]. All participants were community dwelling and had sarcopenia diagnosed by
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poor physical performance and low muscle mass as measured by bio-impedance. The active group improved more on the chair stand test, a test of lower limb muscle strength and gained slightly more muscle mass. Whether the effect was
Conclusions
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due to the vitamin D, the protein supplement or both is unknown.
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There is considerable observational evidence that low vitamin D levels are associated with an increased risk of fractures and falls, and the conditions of
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frailty and sarcopenia commonly found in older people. Older people who have multiple diseases with concomitant disability are more likely to have both vitamin D insufficiency and these conditions. The recently discovered observation that low muscle mass and high adipose tissue may further decrease vitamin D levels would suggest that a deleterious cascade may exist between vitamin D levels and frailty and sarcopenia. This would explain the findings from the randomized trials where the beneficial effects of vitamin D supplementation for falls are confined to frail older people with vitamin D insufficiency. There are
ACCEPTED MANUSCRIPT now two studies that have found an increased propensity to fall with high bolus vitamin D supplements underlining the potential risks of achieving nonphysiological levels of vitamin D. As yet it is not clear whether vitamin D supplementation can address the common problems of frailty and sarcopenia,
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but in those patients with these conditions and found to have vitamin D
insufficiency or deficiency it would be prudent to achieve physiological vitamin D
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levels.
ACCEPTED MANUSCRIPT References [1] DeLuca HF. History of the discovery of vitamin D and its active metabolites Bonekey Rep. 2014; 3: 479. [2] Stein MS, Wark JD. An update on the therapeutic potential of vitamin D
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analogues Expert Opin Investig Drugs. 2003 May;12(5):825-40.
[3] Datta P, Philipsen PA, Olsen P, Bogh MK, Johansen P, Schmedes AV, et al. The half-life of 25(OH)D after UVB exposure depends on gender and vitamin D
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receptor polymorphism but mainly on the start level. Photochem Photobiol Sci. 2017 Jun 14;16(6):985-995
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*[4]Abboud M, Rybchyn MS, Rizk R, Fraser DR, Mason RS. Sunlight exposure is just one of the factors which influence vitamin D status. Photochem Photobiol Sci. 2017 Mar 16;16(3):302-313.
This paper presents data suggesting that low skeletal mass and high levels of
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adipose tissue can lower vitamin D levels
[5] Bolland MJ, Jackson R, Gamble GD, Grey A. Discrepancies in predicted
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fracture risk in elderly people. BMJ. 2013; 346:e8669. [6] de Jongh RT, van Schoor NM, Lips P. Changes in vitamin D endocrinology
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during aging in adults. Mol Cell Endocrinol. 2017 Sep 15;453:144-150 [7] Komar L, Nieves J, Cosman F, Rubin A, Shen V, Lindsay R. Calcium homeostasis of an elderly population upon admission to a nursing home. J Am Geriatr Soc. 1993; 41:1057-64. [8] Lips P, Duong T, Oleksik A, Black D, Cummings S, Cox D, Nickelsen T. A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the multiple outcomes of raloxifene evaluation clinical trial. J Clin Endocrinol Metab. 2001; 86:1212-21
ACCEPTED MANUSCRIPT [9] Avenell A, Mak JCS, O'Connell D. Vitamin D and vitamin D analogues for preventing fractures in post‐menopausal women and older men. Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD000227. DOI: 10.1002/14651858.CD000227.pub4
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[10] Sanders KM, Stuart AL, Williamson EJ, Simpson JA, Kotowicz MA, Young D, et al. Annual high‐dose oral vitamin D and falls and fractures in older women. A
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Engl J Med 2012; 367:40-9
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A Pooled Analysis of Vitamin D Dose Requirements for Fracture Prevention N
[12] Tinetti ME, Speechley M, Ginter SF. Risk factors for falls among elderly persons living in the community. N Engl J Med. 1988; 319:1701-7
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[13] Lord SR, Ward JA, Williams P, Anstey KJ. Physiological factors associated with falls in older community-dwelling women. J Am Geriatr Soc. 1994; 42:11107
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[14] Bouillon R, Marcocci C, Carmeliet G, Bikle D, White JH, Dawson-Hughes B, Lips P, Munns CF, Lazaretti-Castro M, Giustina A, Bilezikian J.
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Skeletal and extra-skeletal actions of vitamin D: Current evidence and outstanding questions. Endocr Rev. 2018 Oct 12. doi: 10.1210/er.2018-00126. [15] Garcion E, Wion-Barbot N, Montero-Menei CN, Berger F, Wion D. New clues about vitamin D functions in the nervous system. Trends Endocrinol Metab. 2002;13:100-5
ACCEPTED MANUSCRIPT [16] Flicker L, Mead K, MacInnis RJ, Nowson C, Scherer S, Stein MS, et al. Serum vitamin D and falls in older women in residential care in Australia. J Am Geriatr Soc. 2003; 51:1533-8 [17] Gillespie LD, Robertson MC, Gillespie WJ, Sherrington C, Gates S, Clemson
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LM, Lamb SE. Interventions for preventing falls in older people living in the
community. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD007146
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*[18] Cameron ID, Dyer SM, Panagoda CE, Murray GR, Hill KD, Cumming RG,
Kerse N. Interventions for preventing falls in older people in care facilities and
CD005465.
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hospitals. Cochrane Database of Systematic Reviews 2018, Issue 9. Art. No.:
This updated meta-analysis found evidence of reduced falls with treatment using vitamin D supplements
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[19] Khaw KT, Stewart AW, Waayer D, Lawes CMM, Toop L, Camargo CA Jr, Scragg R. Effect of monthly high-dose vitamin D supplementation on falls and
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non-vertebral fractures: secondary and post-hoc outcomes from the randomised, double-blind, placebo-controlled ViDA trial. Lancet Diabetes Endocrinol. 2017;
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5:438-447
**[20] Bischoff-Ferrari HA, Dawson-Hughes B, Orav EJ, Staehelin HB, Meyer OW, Theiler R, et al. Monthly High-Dose Vitamin D Treatment for the Prevention of Functional Decline: A Randomized Clinical Trial. JAMA Intern Med. 2016; 176:175-83. This study found an increased rate of falls in those trial participants receiving high doses of vitamin D supplements [21] Morley JE, Vellas B, van Kan GA, et al. Frailty consensus: A call to action. J Am
ACCEPTED MANUSCRIPT Med Dir Assoc 2013;14:392e397. [22] Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: Evidence for a phenotype. J Gerontol A Biol Sci Med Sci 2001;56:M146eM156. [23] Morley JE, Malmstrom TK, Miller DK. A simple frailty questionnaire (FRAIL)
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predicts outcomes in middle aged African Americans. J Nutr Health Aging 2012;16:601e608
measure of aging. Sci World J 2001;1:323e336.
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[24] Mitnitski AB, Mogilner AJ, Rockwood K. Accumulation of deficits as a proxy
[25] Rolfson DB, Majumdar SR, Tsuyuki RT, et al. Validity and reliability of the
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Edmonton Frail Scale. Age Ageing 2006;35:526e529.
[26] Dent E, Lien C, Lim WS, Wong WC, Wong CH, Ng TP, et al. The Asia-Pacific Clinical Practice Guidelines for the Management of Frailty. J Am Med Dir Assoc. 2017; 18:564-575
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[27] Wong YY, McCaul KA, Yeap BB, Hankey GJ, Flicker L. Low vitamin D status is an independent predictor of increased frailty and all-cause mortality in older
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men: The Health in Men Study. J Clin Endocrinol Metab 2013;98:3821e3828. [28] Zhou J, Huang P, Liu P, Hao Q, Chen S, Dong B, Wang J. Association of vitamin
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D deficiency and frailty: A systematic review and meta-analysis. Maturitas 2016; 94:70-76.
[29] Wong YY, Flicker L. Hypovitaminosis D and frailty: epiphenomenon or causal? Maturitas 2015; 82: 328–335. * [30] Anker SD, Morley JE, von Haehling S. Welcome to the ICD-10 code for sarcopenia. J Cachexia Sarcopenia Muscle. 2016; 7:512-514. Sarcopenia is now a listed condition for the ICD-10 classification
ACCEPTED MANUSCRIPT [31] Cruz-Jentoft AJ, Bahat G, Bauer J. Boirie Y, Bruyère O, Cederholm T, et al. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing. 2018 Oct 12. doi: 10.1093/ageing/afy169. [Epub ahead of print] [32] Bauer JM, Verlaan S, Bautmans I, Brandt K, Donini LM, Maggio M, et al.
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Effects of a vitamin D and leucine-enriched whey protein nutritional supplement on measures of sarcopenia in older adults, the PROVIDE study: a randomized,
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double-blind, placebo-controlled trial. J Am Med Dir Assoc. 2015; 16:740-7.