Vitamin D Functions And Changes With Aging

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Vitamin D Functions And Changes With Aging

Vitamin D Functions And Changes With Aging


The need for vitamin D was first established as a treatment for rickets; a disease which causes malformation of bones. However, since the discovery of vitamin D, its necessity virtually throughout the body to maintain optimum health has been established. More recently, focus has been placed on the need for vitamin D in deficient populations such as the elderly to reduce fractures from falling both by strengthening bone and by reducing the preceding sarcopenia elicited from vitamin D’s deficiency. By addressing the underlying sarcopenia with vitamin D supplementation, muscle (particularly Type II A fibers), strength and speed are maintained or regained and falls and resulting fractures are prevented.


Vitamin D3 (cholecalciferol) was discovered in 1936 by German chemist and Nobel laureate, Adolf Windaus, who first characterized 7-dehydrocholesterol, the chemical precursor of vitamin D3. He discovered that it is converted into vitamin D3 in the skin when one of its chemical bonds is broken by the action of sunlight (UVB). This explained why exposure to sunlight can prevent vitamin D3 deficiency (rickets) in humans. Almost simultaneously, a steroid was isolated as the component in cod liver oil responsible for preventing rickets and proved to be identical to vitamin D3. A weaker form of vitamin D found in plants, ergocalciferol, was discovered in 1932 and given the name vitamin D2. Vitamin D3 was first synthesized successfully in 1952.

Physiology and Functions

Vitamin D thus has long been known for its actions on bone; for building strong bones and preventing rickets. But vitamin D is a pleiotropic steroid molecule which acts on more than bone. It has been categorized as a vitamin, but is actually a steroid hormone; synthesized in the body from cholesterol. After its creation from cholesterol into 7-dehydrocholesterol and then its conversion to vitamin D3, “vitamin D3 is hydroxylated in the liver into 25-hydroxyvitamin D3 (25(OH)D) and subsequently in the kidney into 1,25-dihydroxyvitamin D3 (1,25(OH)2D). This is the active metabolite, which stimulates the calcium absorption from the gut.” (1) Simply put, without sufficient vitamin D, insufficient amounts of calcium are absorbed through the intestines from the food we eat, proper bone mineralization does not occur, and rickets, osteoporosis, osteopenia or osteomalacia results.

But this is just part of the story. According to current research summarized by Michael F. Holick, M.D., vitamin D receptors (VDR) “are present not only in the intestine and bone, but in a wide variety of other tissues, including the heart, stomach, pancreas, brain, skin, gonads, and activated T and B lymphocytes. Vitamin D’s active metabolite in the body, (1,25(OH)2D), is one of the most potent substances to inhibit proliferation of both normal and hyperproliferative cells and induce them to mature. Chronic vitamin D deficiency may have serious adverse consequences, including increased risk of hypertension, multiple sclerosis, cancers of the colon, prostate, breast, and ovary, and type 1 diabetes.” (2) Further, “many genes in prostate, colon and breast cancer cells are positively or negatively regulated through the vitamin D receptor.” (3) “In general, 1,25(OH)2D suppresses proliferation and stimulates differentiation of cancer cells, but some exceptions may exist” (4) “Several ecological studies have shown a relationship between lower sunshine exposure and higher cancer prevalence or cancer mortality, e.g. for colon and breast cancer.” (5) “Vitamin D metabolites may also protect against diabetes mellitus type 1 by downregulation of dendritic and Th1 cells, suppression of the antigen-presenting capacity of macrophages and dendritic cells and promotion of Th2 lymphocytes”. (6) “Vitamin D also influences β-cell function. Serum 25(OH)D, the body’s precursor to the active metabolite of vitamin D, 1,25(OH)2D, was positively related to insulin sensitivity and negatively related to first- and second-phase insulin response” (7) “Vitamin D has been shown in various studies to affect scleroderma, congestive heart failure, inflammatory bowel disease, lupus vulgaris, rheumatoid arthritis, and polycystic ovary syndrome.” (8) “The presence of VDR almost ubiquitously in the organism may suggest that the physiologic effect of VDR activation may have a significant role in multiple pathways. Indeed, a role for VDR activation in cell function and tissue development has been demonstrated mainly in bone and muscle (DeLuca et al., 1988) and in lower extent in other tissues such as chondrocytes, liver, and parathyroid cells (Boyan et al., 2004).” (9)

Vitamin D’s Role in Muscle and its Application to the Elderly and Frail

“Two different vitamin D receptors have been reported, one located at the nucleus acting as a classical nuclear receptor and the other more recently discovered VDR located at the membrane (Norman, 1998). The function of these two receptors is significantly different and may have a role in the ways vitamin D acts in bone and muscle.” (10)

Vitamin D’s effect on muscle is relatively newly discovered, but multiple studies bear out the connection; in particular those that focus on the elderly, whose serum vitamin D levels and VDR expression has naturally declined. “As in most of other nuclear receptors, there is a reduction in the number and/or expression of VDR associated with aging (Simpson et al., 1985; Duque et al., 2002). In elderly subjects, serum levels of vitamin D reduce significantly which may have as consequence the reduction in VDR activation and therefore a reduction in their function (Lee et al., 2003). This reduction in VDR expression with aging has been well documented in bowel (Horst et al., 1990), skin (Lehmann et al., 2004) and more interestingly for this review in bone (Duque et al., 2002) and muscle (Bischoff-Ferrari et al., 2004a,b). The significance of the reduction in VDR expression and activity is seen in two age-related pathologies: osteoporosis and osteomalacic myopathy.” (11) More recently, the term sarcopenia is used to describe muscle loss that comes with age in which not only is there atrophy and reduced number of Type II muscle fibers, but a reduced number of Type I muscle fibers. There is an accompanying loss in function that may be accompanied by loss of muscle mass that has been associated with “falls, cognitive decline, depression and mortality.” (12) “Vitamin D deficiency is very common in elderly people, especially in the institutionalized, with a prevalence up to more than 75% in nursing home residents. (13) “Using the large population study, NHANES III, the walking test and the chair stand test were positively influenced (took less time) when serum 25(OH)D was higher. Muscle function was optimal with a 25(OH)D level higher than 60 nmol/l (Bischoff-Ferrari et al., 2004a). The same investigators studied muscle biopsies of 32 women by immunohistochemical staining of the vitamin D receptor and it was observed that the number of vitamin D receptors decreased with aging (Bischoff-Ferrari et al., 2004b). We have also studied vitamin D status and physical performance in the Longitudinal Aging Study Amsterdam. Physical performance was measured by a walk test, chair stands and the tandem stand, a measure for balance, and the score varied between 0 and 12. There was a significant strong positive relationship between serum 25(OH)D and physical performance (Wicherts et al., 2005).” (14) “The protective effect of vitamin D on fractures has been attributed to the established moderate benefit of vitamin D for calcium homeostasis and bone mineral density. However, an alternative explanation might be that vitamin D affects factors directly related to muscle strength and function, thus reducing fracture risk through fall prevention, in addition to its benefits on calcium homeostasis. Extra bone effects are achieved at a muscular level through a strengthening of the muscle mass which improves the balance in senior people.” (15)

“Specifically, in one RCT that compared vitamin D (800 IU/d) plus calcium (1200 mg/d) intakes in institutionalized elderly women with intakes of calcium alone (1200 mg/d), musculoskeletal function improved by 4-11% in the vitamin D plus calcium group (P = 0.0094). In addition, the rate of falling was 49% lower in the vitamin D plus calcium group than in the calcium only group (95% CI: 14%, 71%; P < 0.01. This effect may be mediated by de novo protein synthesis, which affects muscle cell growth through a highly specific nuclear receptor expressed in muscle tissue.” (16) “The genomic effect of vitamin D in muscle includes changes in mRNA that will induce de novo protein synthesis that regulate cell proliferation and induction of terminal differentiation (Boland, 1986).” (17) In one study, it was shown that treatment with vitamin D increased the relative number and size of Type II muscle fibers in elderly women in just 3 months of vitamin D supplementation. (18)

Several studies mentioned by Bischoff-Ferrari et al support vitamin D’s positive effect on muscle and a reduction in the number of falls and an increase in function in the elderly, namely:

Stein MS WJ, Scherer SC, Walton SL, et al. Falls relate to vitamin D and parathyroid hormone in an Australian nursing home and hostel. J Am Geriatr Soc 1999;47:1195-201;

Mowe M, Haug E, Bohmer T. Low serum calcidiol concentration in older adults with reduced muscular function. J Am Geriatr Soc 1999;47(2):220-6;

Pfeifer M, Begerow B, Minne HW, Abrams C, Nachtigall D, Hansen C. Effects of a short-term vitamin D and calcium supplementation on body sway and secondary hyperparathyroidism in elderly women. J Bone Miner Res 2000;15(6):1113-8;

Podsiadlo D, Richardson S. The timed “Up & Go”: a test of basic functional mobility for frail elderly persons. J Am Geriatr Soc 1991;39:142-8.

The studies showing effects of vitamin D supplementation on myopathy are not limited to the elderly. Alyaarubi and Rodd document a case in which “a nearly 5 year old boy presented with proximal muscle weakness, reduced muscle bulk, a positive Gower sign and Trendelenburg gait. He was known to have cholestatic liver disease. Investigations revealed markedly low serum total calcium, elevated alkaline phosphatase, very low serum 25-hydroxyvitamin D, and radiographs consistent with active rickets despite the ongoing administration of a water-soluble preparation of vitamin D. Only i.v. calcitriol acutely correctedthe hypocalcemia, despite trying several oral preparations, suggesting that malabsorption secondary to chronic liver disease was the cause of his rickets.

Intramuscular calciferol quickly corrected his muscle weakness and X-ray findings.” (19)

Practical Requirements and Dosing

The only real question that remains clinically is what serum level of vitamin D3 seems to create the greatest benefit and what amount of supplementation will provide such level. According to US Food and Drug Administration, the DRI for vitamin D3 is 400IU/day regardless of age and makes no recommendations as to healthy serum levels. Bischoff-Ferrari et al recommend a minimum serum concentration and an ideal serum concentration with no gender differences for all those 60 years old or more: “In both active and inactive ambulatory persons aged greater than or equal to 60 years old, 25(OH)D concentrations between 40 and 94 nmol/L are associated with better musculoskeletal function in the lower extremities than are concentrations < 40 nmol/L. For optimal lower-extremity function, it is desirable to reach 25(OH)D concentrations of greater than or equal to 40 nmols/L, and concentrations as high as the upper end of the reference range (90-100 nmol/L) appear to be advantageous.” (20)

Dr. Michael F. Holick cites several studies that support 75 nmol/L as goal for serum vitamin D3. “Because it has been suggested that amounts up to 1000 IU/d of vitamin D, may be needed to maintain a healthy 25(OH)D level of more than 30 ng/mL (75 nmol/L) an intake of 400 IU/d may represent a minimum. This is especially true in the winter or for children and adults not exposed to sunlight. Vitamin D toxicity has not been reported from long-term exposure to sunlight and has only been observed from dietary intake when daily doses exceed 10,000 IU. Doses of 4000 IU/d for 3 months and 50,000 lU/wk for 2 months have been administered without toxicity.” (21)

Summary and Conclusions

While the exact mechanisms are not completely understood, there is sufficient evidence that vitamin D supplementation in adequate doses can be used to stop or slow sarcopenia and osteomalacic myopathy. It can be shown that studies in which this conclusion is not supported, insufficient doses of vitamin D (800IU per day) were used rather than sufficient dosing to bring serum levels above 40 nmols/mL. Considering the effects and the relatively safety and cost of treatment and prevention of sarcopenia with vitamin D, it would seem that its clinical use henceforth be mandatory as part of clinical standards of practice.

1. Feldman, D., Pike, J.W., Glorieux, F.H. (Eds.), 2005. Vitamin D, second ed. Elsevier, Academic Press, London, San Diego.

2. Holick MF. Vitamin D: A millenium perspective. J. Cell. Biochem. 88: 296-307. 2003.

3. S. Nagpal, S. Na and R. Rathnachalan, Noncalcemic actions of vitamin D receptor ligands, Endocrine Rev. 26 (2005), pp. 662-687.

4. G.J. Van den Bemd, H.A. Pols, J.C. Birkenhager, W.M. Kleinekoort and J.P. van Leeuwen, Differential effects of 1,25-dihydroxyvitamin D3-analogs on osteoblast-like cells and on in vitro bone resorption, J. Steroid Biochem. Mol. Biol. 55 (1995), pp. 337-346.

5. Lips, P. Vitamin D physiology. Progress in Biophysics and Molecular Biology. 92, 1, (09/2006) pp 4-8.

6. C. Mathieu, C. Gysemans, A. Giulietti and R. Bouillon, Vitamin D and diabetes, Diabetologica 48 (2005), pp. 1247-1257.

7. K.C. Chiu, A. Chu, V.L. Go and M.F. Saad, Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction, Am. J. Clin. Nutr. 79 (2004), pp. 820-825.

8. Andrew W. Saul, VITAMIN D: Deficiency, Diversity and Dosage, Journal of Orthomolecular Medicine, 2003; Vol. 18, Numbers 3 and 4, p. 194-204

9. M. Montero-Odasso, G. Duque / Molecular Aspects of Medicine 26 (2005) 203-219

10. M. Montero-Odasso, G. Duque / Molecular Aspects of Medicine 26 (2005) 203-219

11. M. Montero-Odasso, G. Duque / Molecular Aspects of Medicine 26 (2005) 203-219

12. Morley, J.E., The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 58:M909-M910 (2003)

13. Holick, M.F., 1994. McCollum award lecture 1994: vitamin D: new horizons for the 21st century. Am. J. Clin. Nutr. 60, 619-630.

14. Lips, P. Vitamin D physiology. Progress in Biophysics and Molecular Biology. 92, 1, (09/2006) pp 4-8.

15. M. Montero-Odasso, G. Duque / Molecular Aspects of Medicine 26 (2005) 203-219

16. Heike A Bischoff-Ferrari, Thomas Dietrich, E John Orav, Frank B Hu, Yuqing Zhang, Elisabeth W Karlson and Bess Dawson-Hughes, Higher 25-hydroxyvitamin D concentrations are associated with better lower-extremity function in both active and inactive persons 60 years and older, American Journal of Clinical Nutrition, Vol. 80, No. 3, 752-758, September 2004

17. M. Montero-Odasso, G. Duque / Molecular Aspects of Medicine 26 (2005) 203-219

18. Sorensen OH, Lund B, Saltin B, et al. Myopathy in bone loss of ageing: improvement by treatment with 1 alpha-hydroxycholecalciferol and calcium. Clinical Science, London 1979;56(2):157-61

19. Alyaarubi S, Rodd C. Treatment of malabsorption vitamin D deficiency myopathy with intramuscular vitamin D. J Pediatr Endocrinol Metab. 2005 Jul;18(7):719-22.

20. Heike A Bischoff-Ferrari, Thomas Dietrich, E John Orav, Frank B Hu, Yuqing Zhang, Elisabeth W Karlson and Bess Dawson-Hughes, Higher 25-hydroxyvitamin D concentrations are associated with better lower-extremity function in both active and inactive persons 60 years and older, American Journal of Clinical Nutrition, Vol. 80, No. 3, 752-758, September 2004

21. Holick, M.F., High Prevalence of Vitamin D Inadequacy and Implications for Health, Mayo Clin Proc. 2006;81(3): 353-373

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