- 25OHD
-
25-hydroxyvitamin D
- 1,25(OH)2D
-
1,25-dihydroxyvitamin D
- VDR
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vitamin D receptor
Aging is accompanied by loss of muscle mass. Each decade, older women lose an average of 0·6 kg lean tissue mass and men lose 1·6 kg( Reference Gallagher, Ruts and Visser 1 ). Loss of muscle mass results in reduced muscle strength and this, in turn, leads to an increased risk of falling. The term sarcopenia was coined in 1989 by Rosenberg to describe the decline in muscle mass that occurs with aging( Reference Rosenberg 2 ). Nine years later, Baumgartner operationalised the term to: appendicular skeletal muscle mass (muscle weight (kg)/height2 (m2) being less than 2 sd below the mean of a young, same-sex reference group( Reference Baumgartner, Koehler and Gallagher 3 ). By this definition, the prevalence of sarcopenia increased from 13 to 24% in persons under the age of 70 years to over 50% in persons over the age of 80 years( Reference Baumgartner, Koehler and Gallagher 3 ). Moreover, he documented the fact that sarcopenia was significantly associated with self-reported physical disability in both men and women, independent of ethnicity, age, morbidity, obesity, income and health behaviours. This study was influential in drawing attention to the extent of the problem and to its ramifications. More recently, a variety of definitions have been proposed but no one is used by all.
Exercise has well-established powerful trophic effects on muscle mass and function. Low intensity self-administered home-based exercise programmes have lowered risk of falling in elders( Reference Campbell, Robertson and Gardner 4 , Reference Bischoff-Ferrari, Dawson-Hughes and Platz 5 ) and should always be encouraged. The focus of this paper, however, is on whether vitamin D status affects muscle performance and risk of falling and whether supplementing current intakes of vitamin D may improve muscle performance and lower risk of falling.
Scope and consequences of falls in the elderly
A major consequence of muscle wasting and atrophy is that it increases risk of falling. Falls are common events and ones that have very serious clinical consequences in the elderly. With aging, fall rates increase by 10% per decade and by the age of 65 years, one in three persons falls each year and by the age of 80 years, one in two falls( Reference Tinetti, Speechley and Ginter 6 ). Of those who fall, 20–30% sustain moderate or severe injuries, at least half of which are fractures( Reference Tinetti, Speechley and Ginter 6 ). Community dwelling elders who have sustained one non-injurious fall have a 3·1-fold increased risk of becoming long-term residents of a nursing home and those who have sustained two or more non-injurious falls have a 5·5-fold increase risk( Reference Tinetti and Williams 7 ). Direct total cost for all fall injuries for people aged 65 and older in the United States exceeded $19 billion in 2000( Reference Stevens, Corso and Finkelstein 8 ). Based on demographic projections, the annual direct and indirect cost of fall injuries may rise to $54·9 billion in 2020( Reference Englander, Hodson and Terregrossa 9 ).
Proposed mechanisms linking vitamin D to muscle performance
Vitamin D in its activated form, 1,25-dihydroxyvitamin D (1,25(OH)2D), acts on muscle by binding to classical nuclear vitamin D receptors (VDR). This binding induces the heterodimerisation of active VDR and a steroid receptor, the retinoic×receptor, forming the VDR/retinoic×receptor/cofactor complex. This complex then binds to vitamin D response elements to regulate gene expression of mRNA and, subsequently, de novo protein synthesis. Mice lacking the VDR show a skeletal muscle phenotype with smaller muscle fibres and persistent immature muscle-gene expression during adult life( Reference Endo, Inoue and Mitsui 10 ). Evidence of the existence of VDR in human muscle stems from a variety of techniques including Western-blot and immunocytochemical analysis using specific antibodies, biochemical characterisation and detection of VDR-mRNA by reverse transcription–PCR( Reference Boland, Norman and Ritz 11 – Reference Santillan, Katz and Vazquez 13 ). VDR in human muscle, measured by immunohistochemical staining have been shown to decline as a function of aging( Reference Bischoff-Ferrari, Borchers and Gudat 14 ). It is not universally agreed, however, that VDR exist in human muscle( Reference HF 15 ).
At the non-genomic level, 1,25(OH)2D acts rapidly at a cell membrane-associated receptor to exert its effects. In chick skeletal muscle cells, this process may involve translocation of the classic nuclear VDR to the cell surface( Reference Capiati, Benassati and Boland 12 ). Alternatively, 1,25(OH)2D may bind to a cell surface 1,25(OH)2D receptor, Membrane Associated Rapid Response Steroid( Reference Boyan, Wang and Wong 16 ) or to another novel 1,25(OH)2D surface receptor( Reference Chen, Olivares-Navarrete and Wang 17 ). It is agreed that 1,25(OH)2D acts at the cell surface to regulate Ca influx by G-protein activation of phospholipase C and adenylate cyclase. This in turn activates the mitogen-activated protein kinase superfamily that regulates muscle cell growth.
Muscle performance and balance
Vitamin D plays a prominent role in muscle health in human subjects. The clinical disorder of vitamin D deficiency is characterised by profound muscle weakness particularly in proximal muscles, and by muscle pain and impaired gait( Reference Glerup, Mikkelsen and Poulsen 18 , Reference Schott and Wills 19 ). Several cross-sectional studies indicate a positive association between serum 25-hydroxyvitamin D (25OHD) concentration and muscle performance in older persons. In 4100 ambulatory adults aged 60 years and older participating in The Third National Health and Nutrition Examination Survey, lower extremity muscle performance, measured as the eight-foot walk test and the repeated sit-to-stand test, was poorest in subjects with the lowest 25OHD levels, below 20 nmol/l, and was progressively higher at increasing 25OHD levels throughout and even beyond the 25OHD reference range( Reference Bischoff-Ferrari, Dietrich and Orav 20 ). A similar association was observed in a prospective cohort of older Dutch men and women( Reference Wicherts, van Schoor and Boeke 21 ). In this study, performance reached its maximum at a mean 25OHD level of 50 nmol/l. This was in contrast to The Third National Health and Nutrition Examination Survey analysis in which performance reached its maximum at 25OHD levels above the upper end of the reference range( Reference Bischoff-Ferrari, Dietrich and Orav 20 ). In the Third National Health and Nutrition Examination Survey, the apparent benefit was independent of gender, level of physical activity and level of Ca intake. Ensrud et al.( Reference Ensrud, Ewing and Fredman 22 ) have described a U-shaped association of 25OHD with frailty in the baseline study measures in older women in the Study of Osteoporotic Fractures. In these women, frailty was minimal at 25OHD levels in the range of 50–75 nmol/l (the base of the U). In a similar analysis in older men in the Osteoporotic Fractures in Men Study, 25OHD was inversely associated with frailty throughout the full range of 25OHD levels, 12–135 nmol/l, although the steepest decline occurred in the range of 12–50 nmol/l( Reference Ensrud, Blackwell and Cauley 23 ).
Randomised, controlled vitamin D intervention trials with muscle performance outcomes have presented a mixed picture, with some studies being positive for selected measures and others being null. Stockton et al.( Reference Stockton, Mengersen and Paratz 24 ) concluded from their meta-analysis that vitamin D had no significant effect on lower extremity muscle strength except in individuals with starting serum 25OHD levels <25 nmol/l. These studies do not provide strong support for a major role for supplemental vitamin D in improving muscle mass or strength in elders with 25OHD levels in the range 25–75 nmol/l, although this possibility remains.
Body sway is used as a measure of balance. Sway, assessed with the subject standing quietly on a force plate, measures ground-reacting force and moments in three orthogonal directions is a reproducible measure of balance and it is a test easily performed by the elderly. These measurements enable the calculation of the maximum displacement in the anteroposterior and medial–lateral directions, the average speed of displacement and other parameters( Reference Swanenburg, de Bruin and Favero 25 ). In adults aged 60 years and older, the root mean square amplitude in the medial–lateral direction was a strong predictor of falling more than once per year( Reference Swanenburg, de Bruin and Uebelhart 26 ). Two independent randomised controlled trials have evaluated the effect of vitamin D on sway. Both trials compared the effect of 20 μg (800 IU) of vitamin D3 plus 1000 mg of Ca/d compared with Ca alone, on sway in elderly adults. The vitamin D groups had an up to 28% improvement (reduction) in body sway( Reference Pfeifer, Begerow and Minne 27 , Reference Pfeifer, Begerow and Minne 28 ) over periods of 2 and 12 months, when compared with the Ca alone groups. These studies implicate a role for vitamin D supplementation in improving balance in elders. This may be an important means by which vitamin D lowers risk of falling.
Falls
A number of organisations now recommend vitamin D to lower risk of falls in the elderly, including the International Osteoporosis Foundation( Reference Dawson-Hughes, Mithal and Bonjour 29 ), the Endocrine Society( Reference Holick, Binkley and Bischoff-Ferrari 30 ) and the US Preventive Services Task Force( Reference Michael, Whitlock and Lin 31 ). In a meta-analysis of randomised controlled trials in community dwelling elders, the US Preventive Services Task Force identified a 17% decrease in risk of falling in the vitamin D compared with the placebo group. In a systematic review, Murad et al.( Reference Murad, Elamin and Abu Elnour 32 ) identified a similar 14% decrease in fall risk with vitamin D compared with placebo. In a meta-analysis limited to high-quality trials (defined on the basis of quality and duration of falls ascertainment during the study), Bischoff-Ferrari et al.( Reference Bischoff-Ferrari, Dawson-Hughes and Staehelin 33 ) examined the impact of the dose of vitamin D administered in the trials. That analysis, involving eight trials and 2426 individuals, revealed that doses of vitamin D up to 15 μg/d (600 IU/d) were ineffective, whereas higher doses that ranged from 17·5–25 μg/d (700–1000 IU/d) reduced risk of falling by about 20%. A recent reanalysis of those trials by the same investigators indicated a 34% risk reduction for the higher 17·5–25 μg/d (700–1000 IU/d) dose trials (OR 0·66 (95% CI 0·53, 0·82)) and no reduction with lower doses of vitamin D (OR 1·14 (95% CI 0·69, 1·87)), with a borderline significant interaction term (P=0·06)( Reference Bischoff-Ferrari 34 ). The reviews cited above reach similar conclusions that vitamin D supplementation in adequate dosage can reduce risk of falling in elders with vitamin D insufficiency. In contrast, the recent Institute of Medicine report (see p. 161) found that ‘ … the greater part of the causal evidence indicated no significant reduction in fall risk related to vitamin D intake or achieved level in blood.’( 35 ).
At this point, the minimum level of 25OHD required for maximal fall-risk reduction is not certain, but the best estimate is that it is about 60 nmol/l. Increases above this level have not added additional protection against falling. In a comparative study of the effect of 20 v. 50 μg/d (800 v. 2000 IU/d) in elderly on fall risk in acute hip fracture patients, the incidence of first falls did not differ significantly in the two treatment groups( Reference Bischoff-Ferrari, Dawson-Hughes and Platz 5 ). Their starting 25OHD levels were 30 nmol/l, and levels at 12 months were 90 nmol/l in the 20 μg/d (800 IU/d) group and 118 nmol/l in the 50 μg/d (2000 IU/d) group. Thus, both groups substantially crossed the proposed threshold of 60 nmol/l and had equal and probably maximal protection against falling. One pragmatic trial testing the effect of an annual oral dose of 12·5 mg (500 000 IU) of vitamin D v. placebo demonstrated that vitamin D actually increased risk of falling; the reason(s) for this are not clear because of the minimal amount of ancillary information and measurements available from the participants( Reference Sanders, Stuart and Williamson 36 ).
The dose of vitamin D needed to achieve a given 25OHD level varies inversely with the starting level of 25OHD and with BMI and other factors that have not been well defined. On average, however, 1 μg (40 IU) of added vitamin D3 will increase the circulating 25OHD level by about 1 nmol/l. Dosing at intervals of daily, weekly and monthly is effective. Less frequent oral dosing, specifically 12·5 mg (500 000 IU) annually, is not recommended in view of the finding of Sanders et al. ( Reference Sanders, Stuart and Williamson 36 ) that it increased falls (and fractures) in older adults.
Conclusions
In conclusion, vitamin D appears to act on muscle tissue through its actions on the VDR but the precise mechanisms involved have not been fully defined. Its effects on performance are most apparent in individuals with lower initial 25OHD levels. Vitamin D also affects balance, but the mechanisms for this are less clear. Adequate vitamin D status is important to lower the risk of falling in older men and women. It appears at this time that a circulating 25OHD level of at least 60 nmol/l is needed to minimise fall risk, but additional research is needed to confirm this.
Acknowledgements
This manuscript preparation was supported by contract 58-1950-7-707 from the US Department of Agriculture. This article does not necessarily reflect the views or policies of the US Department of Agriculture, nor does mention of trade names, commercial products or organisations imply endorsement by the US government. The author has no known conflict of interest.
