Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health, vol. -, no. -, 1e5, 2015 Ó Copyright 2015 by The International Society for Clinical Densitometry 1094-6950/-:1e5/$36.00 http://dx.doi.org/10.1016/j.jocd.2015.04.015
Original Article
Vitamin D and Sarcopenia/Falls Joan M. Lappe,*,1 and Neil Binkley2 1
Osteoporosis Research Center, Department of Medicine, Creighton University, Omaha, NE, USA; and 2Osteoporosis Clinical Research Program, Department of Medicine, University of Wisconsin, Madison, WI, USA
Abstract Maintenance of adequate vitamin D status is a stratagem to consider for sarcopenia prevention and treatment. Vitamin D deficiency is common and involves all ages of most racial/ethnic groups and both sexes. Evidence suggests that vitamin D is important for muscle strength and function, and prospective studies are underway to further define these effects. This article summarizes the potential effects of vitamin D on skeletal muscle structure and function and provides guidance for vitamin D supplementation in prevention and treatment of sarcopenia and falls. Key Words: Falls; muscle function; sarcopenia; vitamin D.
Introduction
Vitamin D Deficiency
Accumulating evidence suggests that maintenance of adequate vitamin D status may be one stratagem in sarcopenia prevention and treatment. Interestingly, this is not a new concept because the sun’s rays were considered a source of physical strength and vitality long before the relationship between sunlight and vitamin D was recognized. For example, the rays of Amon-Rah, the ancient Egyptian’s Sun God, were able to render ‘‘a single man stronger than a crowd’’ (1). Similarly, the ancient Greeks recommended exposure to sunlight as a remedy for weak and flabby muscles, and ancient Olympians’ training included lying exposed and exercising under the sun’s rays. Vitamin D is classically known for its role in bone and mineral homeostasis. However, in the past decade, novel biological activities of vitamin D, importantly including muscle function, have been described, thereby allowing recognition of potential wide-ranging effects beyond calcium homeostasis. This article summarizes the potential effects of vitamin D on skeletal muscle structure and function and provides guidance for vitamin D supplementation in prevention and treatment of sarcopenia and falls.
Vitamin D deficiency is common, spanning all continents, and involves all ages of most racial/ethnic groups and both sexes. Specifically, low circulating 25-hydroxyvitamin D (25 [OH]D), the functional indicator of vitamin D status, is present in approx 26% of noninstitutionalized Americans older than 70 yr. The prevalence of vitamin D deficiency is higher in homebound and institutionalized older adults. Females are at higher risk of deficiency than males, and non-Hispanic black and Mexican Americans are at higher risk than non-Hispanic white individuals. The racial/ethnic differences are largely because of the inverse association between skin pigmentation and 25(OH)D. Low vitamin D status is also related to seasonal changes, latitude, and aging. Factors associated with the increase in vitamin D deficiency include decreased sunlight exposure, use of sunscreen that interferes with cutaneous vitamin D production, low oral vitamin D intakes, and the upward spiral in body mass index. It has been suggested that the worldwide increase in obesity is a major contributory factor to growing epidemic of vitamin D deficiency.
Vitamin DdNot Your Typical Vitamin
Received 04/28/15; Accepted 04/29/15. *Address correspondence to: Joan M. Lappe, PhD, Osteoporosis Research Center, Department of Medicine, Creighton University, 601 North 30th St, Suite 4820, Omaha, NE 68131. E-mail: [email protected]
Vitamin D is not a true vitamin, that is, it is not an essential dietary factor. Rather, it is an endogenously produced secosteroid with a molecular structure similar to classic steroid hormones (e.g., estradiol, cortisol, and aldosterone). Vitamin D carries out essential biologic functions via endocrine and autocrine pathways. Vitamin D3 (cholecalciferol) is produced in 1
2 the skin on exposure to ultraviolet B radiation, which converts 7-dehydrocholesterol to previtamin D3, followed by thermally induced transformation to vitamin D3 (cholecalciferol). Vitamin D2 (ergocalciferol) is produced by irradiation of plant sterols. Vitamin D, whether dietary or skin produced, is metabolized in the liver by 25-D hydroxylase to 25(OH) D. Serum 25(OH)D has an approximate 3-wk half-life and is widely recognized as the functional indicator of an individual’s vitamin D status. 25(OH)D is a prohormone and the immediate precursor to the active form of vitamin D; 1,25-dihydroxyvitamin D (1,25(OH)2D, calcitriol). The enzyme CYP27B1-hydroxylase produces 1,25(OH)2D, which is a high-affinity ligand for the vitamin D receptor (VDR). In its endocrine action, 25(OH)D is converted by hydroxylation in the kidney to 1,25(OH)2D, which circulates in the blood as a hormone to regulate bone and mineral homeostasis. A primary target of 1,25(OH)2D is the intestinal mucosa, where it facilitates calcium absorption. The discovery that vitamin D also acts through an autocrine pathway has stimulated considerable interest and research. In this system, 25(OH)D is converted to 1,25(OH)2D intracellularly by 1-a-hydroxylases in numerous tissues. When these cells receive an extracellular signal to produce proteins, enzymes, or signaling molecules, 1,25(OH)2D binds to the VDR, and, in combination with tissue- and stimulus-specific proteins, binds to vitamin D response elements on the chromosomes, inducing transcription of needed substances. In this manner, 1,25(OH)2D serves as an intermediary between external stimuli and genomic response. Adequate circulating 25(OH)D levels are essential for this local conversion of 25(OH)D to 1,25(OH)2D. Vitamin D 24-hydroxylase, which degrades excess 1,25(OH)2D intracellularly thereby preventing excess accumulation, is also produced in cells possessing 1-a-hydroxylase. In this manner, vitamin D serves as a quick on-off switch, necessary for expression of certain cellular actions but also limiting their duration and extent. This model illustrates 1 key role of vitamin D in mediating cellular responses to external signals.
Could Vitamin D Affect Muscle Function and/or Contribute to Sarcopenia Development? dPotential Mechanisms Low vitamin D status has long been recognized to cause muscle weakness (see later). However, controversy exists about how this may occur and whether the effects of vitamin D on muscle function are genomic, nongenomic, or both. This controversy is fueled by recent work that failed to find the VDR in skeletal, smooth, or cardiac muscle, whereas others report finding the VDR in muscle cells. If the VDR is in fact present, vitamin D could have direct genomic effects on muscle function. In contrast, if VDR is not present in muscle, any vitamin D effect must be mediated by a currently unappreciated receptor or be indirect. A potential indirect effect is hypophosphatemia caused by severe vitamin D deficiency. Vitamin D stimulates phosphate absorption and reduces
Lappe and Binkley parathyroid hormone (PTH), thereby reducing renal phosphate loss; a combination that increases serum phosphate. Indeed, phosphate repletion corrects muscle weakness in vitamin D-deficient rats; whether the same is true in humans remains unknown. However, it is plausible that the falls risk reduction reported in older adults after vitamin D supplementation is due only to correcting hypophosphatemia in those with severe vitamin D deficiency. Thus, the mechanism(s) by which vitamin D may affect muscle function and potentially sarcopenia development remains unclear.
Vitamin D and MuscledClinical Studies Severe vitamin D deficiency causes muscle pain and wasting with resultant weakness and waddling gait that is improved by vitamin D treatment. However, it is unclear if a less severe vitamin D lack, that is, inadequacy impairs muscle/physical performance. Some data do suggest that vitamin D inadequacy may impair muscle function and is associated with sarcopenia (2). Moreover, low 25(OH)D is associated with lower muscle mass, poorer performance in functional testing, and predicts greater muscle loss and disability development (3). Whether these relationships are simply associational or whether vitamin D inadequacy causes muscle weakness remains to be defined. Indeed, some, but not all, randomized prospective studies find vitamin D supplementation to increase muscle strength (4). To briefly review the existing data, some cross-sectional and observational studies find low 25(OH)D to be associated with lower lean mass and with greater muscle loss (2,5). Consistent with a direct effect of vitamin D, some small prospective studies do find vitamin D supplementation to increase type II muscle fiber number and cross-sectional area. In contrast, others find no association of 25(OH)D with muscle mass or strength. Meta-analyses are conflicting, finding supplemental vitamin D to have beneficial effects on strength and balance (6) or no effect on strength (7). It is not surprising that meta-analyses have failed to clarify the role of vitamin D inadequacy with muscle function. This lack of clarity likely reflects multiple confounders and design concerns in existing studies. An important limitation of most studies is nonrecognition that the serum 25(OH)D response to vitamin D supplementation is highly variable. It is self-evident that individuals who receive vitamin D supplementation but do not alter their serum 25(OH)D would not be expected to experience a biologic effect. In summary, existing data suggest that vitamin D inadequacy is associated with poorer muscle function and muscle loss. However, additional properly designed randomized clinical trials (RCTs) are necessary to further clarify the relationship of vitamin D status and muscle function.
Vitamin D and Falls Falls in older adults are associated with loss of muscle mass and strength. Vitamin D might improve physical performance and reduce falls risk via muscular effects as noted previously but also (potentially) by nonmuscular effects, for
Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health
Volume
-,
2015
Sarcopenia and Vitamin D example, by improving neural performance and/or balance. For example, vitamin D may improve reaction time, and fallers have slower reaction times than nonfallers. Because vestibular function is impaired in VDR knockout mice, vitamin D deficiency might alter vestibular function leading to poorer balance and increased falls risk. Indeed, higher 25(OH)D is associated with better balance and lower body sway, and vitamin D supplementation reduced body sway in those with elevated sway. Regardless of the mechanism(s), most, but not all, observational studies of falls and serum 25(OH)D find an inverse association. However, rather than establishing direct causality, it is possible that low 25(OH)D in these studies is simply a marker for comorbidities rather than a direct cause of falls. Numerous RCTs have been conducted in an attempt to determine the effect of vitamin D supplementation on falls. Meta-analyses of these RCTs find a positive effect of vitamin D ranging from a 14% to 34% decrease in falls incidence. A recent meta-analysis of 26 RCTs including 45,782 older adults, primarily females, concluded that vitamin D supplementation reduced the risk of falls by about 14% (8). This effect was seen in both community-dwelling and institutionalized persons. The effect was strongest in persons who were vitamin D deficient at baseline and in studies that gave calcium in combination with vitamin D. On the other hand, other meta-analyses have found no effect. Because of variation among the studies and design flaws, the studies did not provide adequate information to guide the choice of vitamin D supplement doses or to identify the target serum levels required to prevent falls. A large National Institutes of Health-funded study is currently underway, hopefully, to provide more insight to these important questions. Pending the results of such RCTs, the American Geriatrics Society (AGS) consensus statement recently concluded that a serum 25(OH)D of 30 ng/mL should be a minimum goal in older adults to reduce falls and related injuries (9).
3 PTH concentrations tend to plateau at serum 25(OH)D levels of 28e40 ng/mL (70e100 nmol/L). An optimal level of at least 30e32 ng/mL (75e80 nmol/L) is also suggested by the relationship between 25(OH)D and both bone mineral density and lower extremity neuromuscular function in National Health and Nutrition Examination Survey III. Last, highly sun-exposed individuals have 25(OH)D values of about 40e50 ng/mL (100e125 nmol/L), and some studies find that 25(OH)D as high as 80 ng/mL (200 nmol/L) can be achieved by cutaneous production (10,11). The Institute of Medicine recommends that a serum 25(OH)D level of at least 20 ng/mL (50 nmol/L) meets the requirements for bone health (12). However, the recent AGS consensus statement recommends that a serum 25(OH)D level of 30 ng/mL (75 nmol/L) should be a minimum goal for older adults, particularly those who are at risk for falls, injuries, and fractures (9). An important consideration for interpreting a patient’s serum 25(OH)D result is that variability in serum 25(OH)D assays continues to exist. The Office of Dietary Supplements Vitamin D Standardization Program, in concert with other organizations worldwide, is striving to improve 25(OH)D measurement. However, even in laboratories that meet current Vitamin D Standardization Program guidelines, a single 25(OH)D value of 30 ng/mL could be between w24 and w36 ng/mL (Fig. 1). Based on such variability, combined with lack of toxicity, it has been suggested that clinicians strive for 25(OH)D levels of w40 ng/mL (100 nmol/L) in their patients. This should assure a true 25(OH)D value above 30 ng/mL (75 nmol/L) without exposing patients to extremely high levels.
Defining and Achieving Optimal Levels of 25(OH)D The definition of optimal serum 25(OH)D and the levels at which to define vitamin D deficiency and/or inadequacy are extremely controversial. For decades, the index disease for vitamin D deficiency in adults was osteomalacia, which is associated with serum 25(OH)D concentrations !w8 ng/ mL (20 nmol/L). The Institute of Medicine report is generally congruent with this approach, stating that individuals with 25(OH)D levels of 12 ng/mL are at risk of deficiency. Given the uncertainty with defining low, it is unsurprising that normal ranges for serum 25(OH)D in US clinical laboratories are variable and range from 20 to 100 ng/mL. Despite the controversy, virtually all experts and organizations agree that 25(OH)D levels below 20 ng/mL (50 nmol/L) are low. However, some experts argue that the optimal range for 25(OH)D values is above 30e32 ng/mL (75e80 nmol/L) for most populations. Such arguments are based on the inverse relationship between PTH and 25(OH)D, showing that
Fig. 1. Variability associated with a single 25(OH)D measurement. The Vitamin D Standardization Program currently suggests assay performance limits for clinical laboratories that allow a coefficient of variation (%CV) of up to 10%. Assays meeting this criterion would be deemed acceptable. The effect of this variability on a single 25(OH)D value reported as 30 ng/mL is shown here; the true value lies between 24 and 36 ng/mL (Data and figure from C. Sempos, PhD, used with permission). Based on such assay variability, it is recommended that clinicians target 40 ng/mL. 25(OH)D, 25hydroxyvitamin D.
Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health
Volume
-,
2015
4
Considerations for Vitamin D Supplementation What dose to use and what type of vitamin D to supplement are hot topics. In the field of sarcopenia and falls risk reduction, this controversy is fueled by equivocal findings of vitamin D supplementation trials because of study limitations that include providing supplements to those who are not deficient, use of suboptimal physical function measures, and by the provision of fixed vitamin D doses, an approach that produces markedly different changes in serum 25(OH) D among individuals. Indeed, some people experience little or no increase in serum 25(OH)D after what many would consider high-dose vitamin D supplementation (Fig. 2). Some of this variability is likely because of genetic differences. However, variation is also known to be because of factors, such as malabsorption, use of medications affecting vitamin D metabolism, and high body mass or obesity. Because obese persons require more vitamin D than normal-weight persons to attain the same increase in serum 25(OH)D, it has been suggested that obese persons be given higher doses of vitamin D supplementation (6000e10,000 IU/d) for treatment and prevention of vitamin D deficiency (13). As a result of the variation of serum 25(OH)D after supplementation, in a given patient, it is reasonable to repeat 25(OH)D measurement approx 4e6 mo after provision of supplementation. Achieving and maintaining optimal levels of serum 25(OH)D by diet alone is challenging because few foods are natural sources of vitamin D and fortified foods contain only small amounts. The major source of vitamin D is widely assumed to be sunlight exposure. Exposing arms and legs for 5e30 min between 10:00 AM and 3:00 PM may meet vitamin D
Fig. 2. Variability of 25(OH)D response to oral supplementation. The figure demonstrates that the 25(OH)D increase after oral vitamin D3 supplementation varies greatly between individuals. These 25 postmenopausal women received 2300 IU of vitamin D3 daily for 4 mo and were selected for presentation here because they were 95%e100% compliant with supplementation. Serum 25(OH)D was measured at baseline and 4 mo follow-up; between-individual variability is apparent. 25(OH)D, 25-hydroxyvitamin D.
Lappe and Binkley requirements. However, variables, such as season, latitude, clothing, sunscreen use, skin pigmentation, and age, affect the amount of vitamin D produced in the skin. Widespread concern about skin cancer and photoaging results in sun avoidance and widespread use of sunscreen. At latitudes above 37 N, the solar angle is low enough such that no vitamin D is produced in the skin from about mid-October to mid-March. Although some vitamin D obtained from summer sunlight is stored, many individuals do not store enough to maintain 25(OH)D levels through the winter months. As such, vitamin D supplements are often necessary. Vitamin D supplements are widely available as nonprescription in the form of either vitamin D3 or D2 in doses ranging from 400 to 50,000 IU. Most patients have little difficulty with compliance with vitamin D supplementation. Some evidence suggests that vitamin D is absorbed better when taken with food. At this time, reasonable guidance for vitamin D supplementation in older adults is provided by the AGS consensus statement on Vitamin D for the Prevention of Falls and Their Consequences published in 2013 (9). The goal of this consensus statement was to help primary care providers achieve adequate vitamin D from all sources in their older patients. The group based their conclusions on extensive reviews of evidence for fall and fracture reduction in clinical trials of older adults, both community dwelling and institutionalized. The abstract and full report are available at www.geriatricscareonline.org. A brief overview of the AGS consensus recommendations is as follows: For reducing falls and fractures in older persons, the consensus statement advised that clinicians recommend vitamin D supplementation of at least 1000 IU/d, and calcium supplementation, to both community-dwelling and institutionalized older adults. This was based on findings that many older adults have low serum 25(OH)D levels, and vitamin D doses below 600 IU/d did not prevent falls in RCTs. Most studies showing efficacy included calcium and vitamin D supplementation. For optimizing vitamin D status in older adults, the recommended daily average inputs from all sources (diet, supplements, and sunlight) of 4000 IU/d for all older adults and suggested a starting supplementation dose of 3000 IU daily. The consensus statement also advised that supplement doses should be individualized based on sun exposure, skin pigmentation, and high body mass or obesity, and provided guidance; for details see the consensus statement. In conclusion, low serum 25(OH)D is common in all age groups. Existing, albeit limited, data suggest that vitamin D is important for muscle strength and function, and prospective studies are underway to further define these effects. At this time, the bulk of prospective trial evidence finds that vitamin D supplementation decreases risk of falling in older adults, although the mechanism(s) are not understood. Evidencebased guidelines recommend a daily average vitamin D input
Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health
Volume
-,
2015
Sarcopenia and Vitamin D from all sources of 4000 IU/d for all older adults with a serum 25(OH)D level of 30 ng/mL (75 nmol/L) as a minimum goal, particularly for those who are at risk for falls, injuries, and fractures. Vitamin D supplementation is safe, inexpensive, and well tolerated. Thus, it is prudent that clinicians consider vitamin D status in their care of older adults.
5
4. 5.
6.
Key Points Low vitamin D status is epidemic. Vitamin D is likely needed for muscle strength and function. Research supports that vitamin D supplementation reduces falls risk. Many individuals require supplementation to maintain adequate levels of vitamin D. An evidence-based guideline recommends a daily average vitamin D input of 4000 IU/d from all sources for all older adults.
References 1. Girgis C, Clifton-Bligh R, Hamrick M, et al. 2013 The roles of vitamin D in skeletal muscle: form, function, and metabolism. Endocr Rev 34(1):33e83. 2. Scott D, Blizzard L, Fell J, et al. 2010 A prospective study of the associations between 25-hydroxy-vitamin D, sarcopenia progression and physical activity in older adults. Clin Endocrinol (Oxf) 73(5):581e587. 3. Tieland M, Brouwer-Brolsma EM, Nienaber-Rousseau C, et al. 2013 Low vitamin D status is associated with reduced muscle
7. 8. 9.
10. 11. 12.
13.
mass and impaired physical performance in frail elderly people. Eur J Clin Nutr 67(10):1050e1055. Bischoff-Ferrari HA, Willett WC, Orav EJ, et al. 2012 A pooled analysis of vitamin D dose requirements for fracture prevention. N Engl J Med 367(1):40e49. Visser M, Deeg DJ, Lips P. 2003 Low vitamin D and high parathyroid hormone levels as determinants of loss of muscle strength and muscle mass (sarcopenia): the Longitudinal Aging Study Amsterdam. J Clin Endocrinol Metab 88(12):5766e5772. Muir SW, Montero-Odasso M. 2011 Effect of vitamin D supplementation on muscle strength, gait and balance in older adults: a systematic review and meta-analysis. J Am Geriatr Soc 59(12): 2291e2300. Stockton KA, Mengersen K, Paratz JD, et al. 2011 Effect of vitamin D supplementation on muscle strength: a systematic review and meta-analysis. Osteoporos Int 22(3):859e871. Murad M, Elamin K, Abu Elnour N, et al. 2011 The effect of vitamin D on falls: a systematic review and meta-analysis. J Clin Endocrinol Metab 96(10):2997e3006. American Geriatrics Society Workgroup on Vitamin D Supplementation for Older Adults. 2013 Recommendations abstracted from the American Geriatrics Society Consensus Statement on Vitamin D for Prevention of Falls and Their Consequences. J Am Geriatr Soc 62(1):147e152. Binkley N, Novotny R, Krueger D, et al. 2007 Low vitamin D status despite abundant sun exposure. J Clin Endocrinol Metab 92:2130e2135. Barger-Lux J, Heaney R. 2002 Effects of above average summer sun exposure on serum 25-hydroxyvitamin D and calcium absorption fraction. J Clin Endocrinol Metab 87:4952e4956. Institute of Medicine Committee to Review Dietary Reference Intakes for Vitamin D and Calcium. 2011 Dietary reference intakes for calcium and vitamin D. Washington, DC: National Academies Press. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. 2011 Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 96(7):1911e1930.
Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health
Volume
-,
2015
Original Article
Vitamin D and Sarcopenia/Falls Joan M. Lappe,*,1 and Neil Binkley2 1
Osteoporosis Research Center, Department of Medicine, Creighton University, Omaha, NE, USA; and 2Osteoporosis Clinical Research Program, Department of Medicine, University of Wisconsin, Madison, WI, USA
Abstract Maintenance of adequate vitamin D status is a stratagem to consider for sarcopenia prevention and treatment. Vitamin D deficiency is common and involves all ages of most racial/ethnic groups and both sexes. Evidence suggests that vitamin D is important for muscle strength and function, and prospective studies are underway to further define these effects. This article summarizes the potential effects of vitamin D on skeletal muscle structure and function and provides guidance for vitamin D supplementation in prevention and treatment of sarcopenia and falls. Key Words: Falls; muscle function; sarcopenia; vitamin D.
Introduction
Vitamin D Deficiency
Accumulating evidence suggests that maintenance of adequate vitamin D status may be one stratagem in sarcopenia prevention and treatment. Interestingly, this is not a new concept because the sun’s rays were considered a source of physical strength and vitality long before the relationship between sunlight and vitamin D was recognized. For example, the rays of Amon-Rah, the ancient Egyptian’s Sun God, were able to render ‘‘a single man stronger than a crowd’’ (1). Similarly, the ancient Greeks recommended exposure to sunlight as a remedy for weak and flabby muscles, and ancient Olympians’ training included lying exposed and exercising under the sun’s rays. Vitamin D is classically known for its role in bone and mineral homeostasis. However, in the past decade, novel biological activities of vitamin D, importantly including muscle function, have been described, thereby allowing recognition of potential wide-ranging effects beyond calcium homeostasis. This article summarizes the potential effects of vitamin D on skeletal muscle structure and function and provides guidance for vitamin D supplementation in prevention and treatment of sarcopenia and falls.
Vitamin D deficiency is common, spanning all continents, and involves all ages of most racial/ethnic groups and both sexes. Specifically, low circulating 25-hydroxyvitamin D (25 [OH]D), the functional indicator of vitamin D status, is present in approx 26% of noninstitutionalized Americans older than 70 yr. The prevalence of vitamin D deficiency is higher in homebound and institutionalized older adults. Females are at higher risk of deficiency than males, and non-Hispanic black and Mexican Americans are at higher risk than non-Hispanic white individuals. The racial/ethnic differences are largely because of the inverse association between skin pigmentation and 25(OH)D. Low vitamin D status is also related to seasonal changes, latitude, and aging. Factors associated with the increase in vitamin D deficiency include decreased sunlight exposure, use of sunscreen that interferes with cutaneous vitamin D production, low oral vitamin D intakes, and the upward spiral in body mass index. It has been suggested that the worldwide increase in obesity is a major contributory factor to growing epidemic of vitamin D deficiency.
Vitamin DdNot Your Typical Vitamin
Received 04/28/15; Accepted 04/29/15. *Address correspondence to: Joan M. Lappe, PhD, Osteoporosis Research Center, Department of Medicine, Creighton University, 601 North 30th St, Suite 4820, Omaha, NE 68131. E-mail: [email protected]
Vitamin D is not a true vitamin, that is, it is not an essential dietary factor. Rather, it is an endogenously produced secosteroid with a molecular structure similar to classic steroid hormones (e.g., estradiol, cortisol, and aldosterone). Vitamin D carries out essential biologic functions via endocrine and autocrine pathways. Vitamin D3 (cholecalciferol) is produced in 1
2 the skin on exposure to ultraviolet B radiation, which converts 7-dehydrocholesterol to previtamin D3, followed by thermally induced transformation to vitamin D3 (cholecalciferol). Vitamin D2 (ergocalciferol) is produced by irradiation of plant sterols. Vitamin D, whether dietary or skin produced, is metabolized in the liver by 25-D hydroxylase to 25(OH) D. Serum 25(OH)D has an approximate 3-wk half-life and is widely recognized as the functional indicator of an individual’s vitamin D status. 25(OH)D is a prohormone and the immediate precursor to the active form of vitamin D; 1,25-dihydroxyvitamin D (1,25(OH)2D, calcitriol). The enzyme CYP27B1-hydroxylase produces 1,25(OH)2D, which is a high-affinity ligand for the vitamin D receptor (VDR). In its endocrine action, 25(OH)D is converted by hydroxylation in the kidney to 1,25(OH)2D, which circulates in the blood as a hormone to regulate bone and mineral homeostasis. A primary target of 1,25(OH)2D is the intestinal mucosa, where it facilitates calcium absorption. The discovery that vitamin D also acts through an autocrine pathway has stimulated considerable interest and research. In this system, 25(OH)D is converted to 1,25(OH)2D intracellularly by 1-a-hydroxylases in numerous tissues. When these cells receive an extracellular signal to produce proteins, enzymes, or signaling molecules, 1,25(OH)2D binds to the VDR, and, in combination with tissue- and stimulus-specific proteins, binds to vitamin D response elements on the chromosomes, inducing transcription of needed substances. In this manner, 1,25(OH)2D serves as an intermediary between external stimuli and genomic response. Adequate circulating 25(OH)D levels are essential for this local conversion of 25(OH)D to 1,25(OH)2D. Vitamin D 24-hydroxylase, which degrades excess 1,25(OH)2D intracellularly thereby preventing excess accumulation, is also produced in cells possessing 1-a-hydroxylase. In this manner, vitamin D serves as a quick on-off switch, necessary for expression of certain cellular actions but also limiting their duration and extent. This model illustrates 1 key role of vitamin D in mediating cellular responses to external signals.
Could Vitamin D Affect Muscle Function and/or Contribute to Sarcopenia Development? dPotential Mechanisms Low vitamin D status has long been recognized to cause muscle weakness (see later). However, controversy exists about how this may occur and whether the effects of vitamin D on muscle function are genomic, nongenomic, or both. This controversy is fueled by recent work that failed to find the VDR in skeletal, smooth, or cardiac muscle, whereas others report finding the VDR in muscle cells. If the VDR is in fact present, vitamin D could have direct genomic effects on muscle function. In contrast, if VDR is not present in muscle, any vitamin D effect must be mediated by a currently unappreciated receptor or be indirect. A potential indirect effect is hypophosphatemia caused by severe vitamin D deficiency. Vitamin D stimulates phosphate absorption and reduces
Lappe and Binkley parathyroid hormone (PTH), thereby reducing renal phosphate loss; a combination that increases serum phosphate. Indeed, phosphate repletion corrects muscle weakness in vitamin D-deficient rats; whether the same is true in humans remains unknown. However, it is plausible that the falls risk reduction reported in older adults after vitamin D supplementation is due only to correcting hypophosphatemia in those with severe vitamin D deficiency. Thus, the mechanism(s) by which vitamin D may affect muscle function and potentially sarcopenia development remains unclear.
Vitamin D and MuscledClinical Studies Severe vitamin D deficiency causes muscle pain and wasting with resultant weakness and waddling gait that is improved by vitamin D treatment. However, it is unclear if a less severe vitamin D lack, that is, inadequacy impairs muscle/physical performance. Some data do suggest that vitamin D inadequacy may impair muscle function and is associated with sarcopenia (2). Moreover, low 25(OH)D is associated with lower muscle mass, poorer performance in functional testing, and predicts greater muscle loss and disability development (3). Whether these relationships are simply associational or whether vitamin D inadequacy causes muscle weakness remains to be defined. Indeed, some, but not all, randomized prospective studies find vitamin D supplementation to increase muscle strength (4). To briefly review the existing data, some cross-sectional and observational studies find low 25(OH)D to be associated with lower lean mass and with greater muscle loss (2,5). Consistent with a direct effect of vitamin D, some small prospective studies do find vitamin D supplementation to increase type II muscle fiber number and cross-sectional area. In contrast, others find no association of 25(OH)D with muscle mass or strength. Meta-analyses are conflicting, finding supplemental vitamin D to have beneficial effects on strength and balance (6) or no effect on strength (7). It is not surprising that meta-analyses have failed to clarify the role of vitamin D inadequacy with muscle function. This lack of clarity likely reflects multiple confounders and design concerns in existing studies. An important limitation of most studies is nonrecognition that the serum 25(OH)D response to vitamin D supplementation is highly variable. It is self-evident that individuals who receive vitamin D supplementation but do not alter their serum 25(OH)D would not be expected to experience a biologic effect. In summary, existing data suggest that vitamin D inadequacy is associated with poorer muscle function and muscle loss. However, additional properly designed randomized clinical trials (RCTs) are necessary to further clarify the relationship of vitamin D status and muscle function.
Vitamin D and Falls Falls in older adults are associated with loss of muscle mass and strength. Vitamin D might improve physical performance and reduce falls risk via muscular effects as noted previously but also (potentially) by nonmuscular effects, for
Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health
Volume
-,
2015
Sarcopenia and Vitamin D example, by improving neural performance and/or balance. For example, vitamin D may improve reaction time, and fallers have slower reaction times than nonfallers. Because vestibular function is impaired in VDR knockout mice, vitamin D deficiency might alter vestibular function leading to poorer balance and increased falls risk. Indeed, higher 25(OH)D is associated with better balance and lower body sway, and vitamin D supplementation reduced body sway in those with elevated sway. Regardless of the mechanism(s), most, but not all, observational studies of falls and serum 25(OH)D find an inverse association. However, rather than establishing direct causality, it is possible that low 25(OH)D in these studies is simply a marker for comorbidities rather than a direct cause of falls. Numerous RCTs have been conducted in an attempt to determine the effect of vitamin D supplementation on falls. Meta-analyses of these RCTs find a positive effect of vitamin D ranging from a 14% to 34% decrease in falls incidence. A recent meta-analysis of 26 RCTs including 45,782 older adults, primarily females, concluded that vitamin D supplementation reduced the risk of falls by about 14% (8). This effect was seen in both community-dwelling and institutionalized persons. The effect was strongest in persons who were vitamin D deficient at baseline and in studies that gave calcium in combination with vitamin D. On the other hand, other meta-analyses have found no effect. Because of variation among the studies and design flaws, the studies did not provide adequate information to guide the choice of vitamin D supplement doses or to identify the target serum levels required to prevent falls. A large National Institutes of Health-funded study is currently underway, hopefully, to provide more insight to these important questions. Pending the results of such RCTs, the American Geriatrics Society (AGS) consensus statement recently concluded that a serum 25(OH)D of 30 ng/mL should be a minimum goal in older adults to reduce falls and related injuries (9).
3 PTH concentrations tend to plateau at serum 25(OH)D levels of 28e40 ng/mL (70e100 nmol/L). An optimal level of at least 30e32 ng/mL (75e80 nmol/L) is also suggested by the relationship between 25(OH)D and both bone mineral density and lower extremity neuromuscular function in National Health and Nutrition Examination Survey III. Last, highly sun-exposed individuals have 25(OH)D values of about 40e50 ng/mL (100e125 nmol/L), and some studies find that 25(OH)D as high as 80 ng/mL (200 nmol/L) can be achieved by cutaneous production (10,11). The Institute of Medicine recommends that a serum 25(OH)D level of at least 20 ng/mL (50 nmol/L) meets the requirements for bone health (12). However, the recent AGS consensus statement recommends that a serum 25(OH)D level of 30 ng/mL (75 nmol/L) should be a minimum goal for older adults, particularly those who are at risk for falls, injuries, and fractures (9). An important consideration for interpreting a patient’s serum 25(OH)D result is that variability in serum 25(OH)D assays continues to exist. The Office of Dietary Supplements Vitamin D Standardization Program, in concert with other organizations worldwide, is striving to improve 25(OH)D measurement. However, even in laboratories that meet current Vitamin D Standardization Program guidelines, a single 25(OH)D value of 30 ng/mL could be between w24 and w36 ng/mL (Fig. 1). Based on such variability, combined with lack of toxicity, it has been suggested that clinicians strive for 25(OH)D levels of w40 ng/mL (100 nmol/L) in their patients. This should assure a true 25(OH)D value above 30 ng/mL (75 nmol/L) without exposing patients to extremely high levels.
Defining and Achieving Optimal Levels of 25(OH)D The definition of optimal serum 25(OH)D and the levels at which to define vitamin D deficiency and/or inadequacy are extremely controversial. For decades, the index disease for vitamin D deficiency in adults was osteomalacia, which is associated with serum 25(OH)D concentrations !w8 ng/ mL (20 nmol/L). The Institute of Medicine report is generally congruent with this approach, stating that individuals with 25(OH)D levels of 12 ng/mL are at risk of deficiency. Given the uncertainty with defining low, it is unsurprising that normal ranges for serum 25(OH)D in US clinical laboratories are variable and range from 20 to 100 ng/mL. Despite the controversy, virtually all experts and organizations agree that 25(OH)D levels below 20 ng/mL (50 nmol/L) are low. However, some experts argue that the optimal range for 25(OH)D values is above 30e32 ng/mL (75e80 nmol/L) for most populations. Such arguments are based on the inverse relationship between PTH and 25(OH)D, showing that
Fig. 1. Variability associated with a single 25(OH)D measurement. The Vitamin D Standardization Program currently suggests assay performance limits for clinical laboratories that allow a coefficient of variation (%CV) of up to 10%. Assays meeting this criterion would be deemed acceptable. The effect of this variability on a single 25(OH)D value reported as 30 ng/mL is shown here; the true value lies between 24 and 36 ng/mL (Data and figure from C. Sempos, PhD, used with permission). Based on such assay variability, it is recommended that clinicians target 40 ng/mL. 25(OH)D, 25hydroxyvitamin D.
Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health
Volume
-,
2015
4
Considerations for Vitamin D Supplementation What dose to use and what type of vitamin D to supplement are hot topics. In the field of sarcopenia and falls risk reduction, this controversy is fueled by equivocal findings of vitamin D supplementation trials because of study limitations that include providing supplements to those who are not deficient, use of suboptimal physical function measures, and by the provision of fixed vitamin D doses, an approach that produces markedly different changes in serum 25(OH) D among individuals. Indeed, some people experience little or no increase in serum 25(OH)D after what many would consider high-dose vitamin D supplementation (Fig. 2). Some of this variability is likely because of genetic differences. However, variation is also known to be because of factors, such as malabsorption, use of medications affecting vitamin D metabolism, and high body mass or obesity. Because obese persons require more vitamin D than normal-weight persons to attain the same increase in serum 25(OH)D, it has been suggested that obese persons be given higher doses of vitamin D supplementation (6000e10,000 IU/d) for treatment and prevention of vitamin D deficiency (13). As a result of the variation of serum 25(OH)D after supplementation, in a given patient, it is reasonable to repeat 25(OH)D measurement approx 4e6 mo after provision of supplementation. Achieving and maintaining optimal levels of serum 25(OH)D by diet alone is challenging because few foods are natural sources of vitamin D and fortified foods contain only small amounts. The major source of vitamin D is widely assumed to be sunlight exposure. Exposing arms and legs for 5e30 min between 10:00 AM and 3:00 PM may meet vitamin D
Fig. 2. Variability of 25(OH)D response to oral supplementation. The figure demonstrates that the 25(OH)D increase after oral vitamin D3 supplementation varies greatly between individuals. These 25 postmenopausal women received 2300 IU of vitamin D3 daily for 4 mo and were selected for presentation here because they were 95%e100% compliant with supplementation. Serum 25(OH)D was measured at baseline and 4 mo follow-up; between-individual variability is apparent. 25(OH)D, 25-hydroxyvitamin D.
Lappe and Binkley requirements. However, variables, such as season, latitude, clothing, sunscreen use, skin pigmentation, and age, affect the amount of vitamin D produced in the skin. Widespread concern about skin cancer and photoaging results in sun avoidance and widespread use of sunscreen. At latitudes above 37 N, the solar angle is low enough such that no vitamin D is produced in the skin from about mid-October to mid-March. Although some vitamin D obtained from summer sunlight is stored, many individuals do not store enough to maintain 25(OH)D levels through the winter months. As such, vitamin D supplements are often necessary. Vitamin D supplements are widely available as nonprescription in the form of either vitamin D3 or D2 in doses ranging from 400 to 50,000 IU. Most patients have little difficulty with compliance with vitamin D supplementation. Some evidence suggests that vitamin D is absorbed better when taken with food. At this time, reasonable guidance for vitamin D supplementation in older adults is provided by the AGS consensus statement on Vitamin D for the Prevention of Falls and Their Consequences published in 2013 (9). The goal of this consensus statement was to help primary care providers achieve adequate vitamin D from all sources in their older patients. The group based their conclusions on extensive reviews of evidence for fall and fracture reduction in clinical trials of older adults, both community dwelling and institutionalized. The abstract and full report are available at www.geriatricscareonline.org. A brief overview of the AGS consensus recommendations is as follows: For reducing falls and fractures in older persons, the consensus statement advised that clinicians recommend vitamin D supplementation of at least 1000 IU/d, and calcium supplementation, to both community-dwelling and institutionalized older adults. This was based on findings that many older adults have low serum 25(OH)D levels, and vitamin D doses below 600 IU/d did not prevent falls in RCTs. Most studies showing efficacy included calcium and vitamin D supplementation. For optimizing vitamin D status in older adults, the recommended daily average inputs from all sources (diet, supplements, and sunlight) of 4000 IU/d for all older adults and suggested a starting supplementation dose of 3000 IU daily. The consensus statement also advised that supplement doses should be individualized based on sun exposure, skin pigmentation, and high body mass or obesity, and provided guidance; for details see the consensus statement. In conclusion, low serum 25(OH)D is common in all age groups. Existing, albeit limited, data suggest that vitamin D is important for muscle strength and function, and prospective studies are underway to further define these effects. At this time, the bulk of prospective trial evidence finds that vitamin D supplementation decreases risk of falling in older adults, although the mechanism(s) are not understood. Evidencebased guidelines recommend a daily average vitamin D input
Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health
Volume
-,
2015
Sarcopenia and Vitamin D from all sources of 4000 IU/d for all older adults with a serum 25(OH)D level of 30 ng/mL (75 nmol/L) as a minimum goal, particularly for those who are at risk for falls, injuries, and fractures. Vitamin D supplementation is safe, inexpensive, and well tolerated. Thus, it is prudent that clinicians consider vitamin D status in their care of older adults.
5
4. 5.
6.
Key Points Low vitamin D status is epidemic. Vitamin D is likely needed for muscle strength and function. Research supports that vitamin D supplementation reduces falls risk. Many individuals require supplementation to maintain adequate levels of vitamin D. An evidence-based guideline recommends a daily average vitamin D input of 4000 IU/d from all sources for all older adults.
References 1. Girgis C, Clifton-Bligh R, Hamrick M, et al. 2013 The roles of vitamin D in skeletal muscle: form, function, and metabolism. Endocr Rev 34(1):33e83. 2. Scott D, Blizzard L, Fell J, et al. 2010 A prospective study of the associations between 25-hydroxy-vitamin D, sarcopenia progression and physical activity in older adults. Clin Endocrinol (Oxf) 73(5):581e587. 3. Tieland M, Brouwer-Brolsma EM, Nienaber-Rousseau C, et al. 2013 Low vitamin D status is associated with reduced muscle
7. 8. 9.
10. 11. 12.
13.
mass and impaired physical performance in frail elderly people. Eur J Clin Nutr 67(10):1050e1055. Bischoff-Ferrari HA, Willett WC, Orav EJ, et al. 2012 A pooled analysis of vitamin D dose requirements for fracture prevention. N Engl J Med 367(1):40e49. Visser M, Deeg DJ, Lips P. 2003 Low vitamin D and high parathyroid hormone levels as determinants of loss of muscle strength and muscle mass (sarcopenia): the Longitudinal Aging Study Amsterdam. J Clin Endocrinol Metab 88(12):5766e5772. Muir SW, Montero-Odasso M. 2011 Effect of vitamin D supplementation on muscle strength, gait and balance in older adults: a systematic review and meta-analysis. J Am Geriatr Soc 59(12): 2291e2300. Stockton KA, Mengersen K, Paratz JD, et al. 2011 Effect of vitamin D supplementation on muscle strength: a systematic review and meta-analysis. Osteoporos Int 22(3):859e871. Murad M, Elamin K, Abu Elnour N, et al. 2011 The effect of vitamin D on falls: a systematic review and meta-analysis. J Clin Endocrinol Metab 96(10):2997e3006. American Geriatrics Society Workgroup on Vitamin D Supplementation for Older Adults. 2013 Recommendations abstracted from the American Geriatrics Society Consensus Statement on Vitamin D for Prevention of Falls and Their Consequences. J Am Geriatr Soc 62(1):147e152. Binkley N, Novotny R, Krueger D, et al. 2007 Low vitamin D status despite abundant sun exposure. J Clin Endocrinol Metab 92:2130e2135. Barger-Lux J, Heaney R. 2002 Effects of above average summer sun exposure on serum 25-hydroxyvitamin D and calcium absorption fraction. J Clin Endocrinol Metab 87:4952e4956. Institute of Medicine Committee to Review Dietary Reference Intakes for Vitamin D and Calcium. 2011 Dietary reference intakes for calcium and vitamin D. Washington, DC: National Academies Press. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. 2011 Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 96(7):1911e1930.
Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health
Volume
-,
2015
