Vitamin D and the Elderly

Leif Mosekilde

Disclosures

Clin Endocrinol. 2005;62(3):265-281. 

In This Article

Summary and Introduction

Summary

This review summarizes current knowledge on vitamin D status in the elderly with special attention to definition and prevalence of vitamin D insufficiency and deficiency, relationships between vitamin D status and various diseases common in the elderly, and the effects of intervention with vitamin D or vitamin D and calcium. Individual vitamin D status is usually estimated by measuring plasma 25-hydroxyvitamin D (25OHD) levels. However, reference values from normal populations are not applicable for the definition of vitamin D insufficiency or deficiency. Instead vitamin D insufficiency is defined as the lowest threshold value for plasma 25OHD (around 50 nmol/l) that prevents secondary hyperparathyroidism, increased bone turnover, bone mineral loss, or seasonal variations in plasma PTH. Vitamin D deficiency is defined as values below 25 nmol/l. Using these definitions vitamin D deficiency is common among community-dwelling elderly in the developed countries at higher latitudes and very common among institutionalized elderly, geriatric patients and patients with hip fractures. Vitamin D deficiency is an established risk factor for osteoporosis, falls and fractures. Clinical trials have demonstrated that 800 IU (20 μg) per day of vitamin D in combination with 1200 mg calcium effectively reduces the risk of falls and fractures in institutionalized patients. Furthermore, 400 IU (10 μg) per day in combination with 1000 mg calcium or 100 000 IU orally every fourth month without calcium reduces fracture risk in individuals over 65 years of age living at home. Yearly injections of vitamin D seem to have no effect on fracture risk probably because of reduced bioavailability. Simulation studies suggest that fortification of food cannot provide sufficient vitamin D to the elderly without exceeding present conventional safety levels for children. A combination of fortification and individual supplementation is proposed. It is argued that all official programs should be evaluated scientifically. Epidemiological studies suggest that vitamin D insufficiency is related to a number of other disorders frequently observed among the elderly, such as breast, prostate and colon cancers, type 2 diabetes, and cardiovascular disorders including hypertension. However, apart from hypertension, causality has not been established through randomized intervention studies. It seems that 800 IU (20 μg) vitamin D per day in combination with calcium reduces systolic blood pressure in elderly women.

Introduction

Strictly speaking, vitamin D is not a vitamin because it is produced in adequate quantities in the skin depending on sufficient sun [ultraviolet B (UVB)] exposure and exposed skin surface.[1] The dermal production is regulated so that inactive metabolites (tachysterol and lumisterol) are produced at times of excess UVB exposure. Vitamin D.3 is, by itself, sensitive to irradiation and is thereby inactivated to suprasterol 1 and 2 and to 5,6-trans-vitamin D3. Furthermore, vitamin D production depends on skin pigmentation,[2,3] both natural and caused by sunburn, the latter creating a type of negative feedback loop. Hence, vitamin D should probably be considered a hormone produced in the skin and metabolized to more active compounds in peripheral tissue in the same way as thyroxine is converted to triiodothyronine in liver, kidney and other tissues. In the liver vitamin D is hydroxylated to 25-hydroxyvitamin D (25OHD),[4] which is further 1α-hydroxylated to 1,25(OH)2D in the kidney. 5 Recent studies have disclosed that before the 1-hydroxylation, 25OHD and vitamin D-binding protein (DBP) are filtered in the kidney and reabsorbed in the proximal renal tubules by megalincubilin receptors.[6] The renal hydroxylation is closely regulated, being enhanced by PTH, hypocalcaemia and hypophosphataemia and inhibited by 1,25(OH)2D itself.[4] 1,25(OH)7D regulates gene transcription through a nuclear high-affinity vitamin D receptor (VDR)[8,9] and initiation of rapid cellular responses through a putative plasma membrane-associated receptor membrane.[10] The receptors are located in classical target organs such as the intestine, bone, kidney and parathyroid, as well as in many other tissues and cell types, 7 including the immune system.[11] Vitamin D is deposited in adipose tissue, but the depot is not large enough or sufficiently regulated to prevent seasonal variations in plasma concentrations of 25OHD and PTH (Fig. 1).[12,13]

When vitamin D levels are low, compensatory secondary hyperparathyroidism increases the renal conversion of 25OHD and thereby maintains normal or slightly increased plasma levels of 1,25(OH)2D until the vitamin D deficiency is severe enough (frank osteomalacia) to reduce the level of this metabolite.[14] Low plasma 25OHD and secondary hyperparathyroidism are therefore the biochemical hallmarks for insufficient vitamin D status.[14,15] Furthermore, recent research has demonstrated that various normal human tissues and cell lines possess 25OHD-1β-hydroxylase activity and have the capacity to convert 25OHD directly to 1,25(OH)2D to satisfy local needs in a paracrine way.[16,17,18] This production probably depends on the availability of circulating 25OHD, indicating the biological importance of sufficient plasma levels of this vitamin D metabolite.

Humans have a considerable ability to adapt to altered living conditions either through a slow genetic selection or faster through altered lifestyle, diet (including food fortification) or pharmacological intervention. The naked ape was probably, like the nonhuman primates, well adapted to its sun-rich tropical environment. 1 Following the exodus from Africa, the northern latitudes were inhabited by fair-skinned people with an increased ability to make use of the limited amount of UVB despite the need for clothing. By contrast, dark-skinned recent immigrants from Palestine, Pakistan and India to Northern Europe may develop severe vitamin D deficiency with proximal myopathy because of the limited effect of sunshine and a low dietary vitamin D intake.[19,20] This problem has triggered pharmacological substitution programs with limited effect.[21,22] By contrast, moderately pigmented Inuits during their migration towards the Polar regions through millenniums have adapted to a life with sparse solar exposure through a diet of fatty fish and blubber with a high content of animal vitamin D. Furthermore, they have genetically developed an enhanced renal conversion of 25OHD to 1,25(OH)2D, improving the use of available vitamin D.[23] By contrast, Asian Indians have developed (or maintained) an increased renal 24,25(OH)2D-hydroxylase activity facilitating the production of the inactive 24,25(OH)2D at the expense of 1,25(OH)2D.[24]

The elderly populations of Europe, the USA and Australia, however, present special problems.[15,25,26,27] With increasing age, solar exposure is usually limited because of changes in lifestyle factors such as clothing and outdoor activity. Diet may also become less varied, with a lower natural vitamin D content. Most importantly, however, the dermal production of vitamin D following a standard exposure to UVB light decreases with age because of atrophic skin changes with a reduced amount of its precursor.[2,28] Finally, the renal production of 1,25(OH)2D decreases because of diminishing renal function with age.[29] These changes in vitamin D metabolism render the ageing population in general at risk of vitamin D deficiency, especially in winter seasons and when living indoor and at higher latitudes.[15] This deficiency may lead to severe consequences in terms of falls, osteoporosis and fractures.

In this review I describe vitamin D-related problems among the elderly, essentially focusing on the definition and prevalence of vitamin D deficiency and the effects of vitamin D on risks of falling, osteoporosis and fractures. I have concentrated on randomized controlled studies demonstrating causality between vitamin D and outcome events. However, I have also included epidemiological studies on cancer risk and associations with other common diseases among the elderly, such as type 2 diabetes and cardiovascular disease. I have deliberately excluded the potential favorable influence of UVB radiation and vitamin D status or supplementation on the occurrence of other disorders such as pneumonia,[30] tuberculosis,[31] periodontal disease,[32] type 1 diabetes,[33,34,35,36] rheumatoid arthritis,[37] inflammatory bowel disorders[38,39,40] and multiple sclerosis,[41,42] as these disorders are not specific for the elderly.

For the present narrative review I have searched PubMed 1990-2004 and EMBASE 19902004 using the MESH terms 'calcifediol', 'calcitriol' and 'Vitamin D' in combination with 'osteoporosis', 'fractures', 'falls', 'cancer', 'diabetes', 'hypertension' and 'cardiovascular disease' to July 2004. I have screened all the abstracts and included those of interest. I have also screened reference lists of review papers covering the period 2000-04 for more papers of interest.

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