Alfred Denio, MD
Prior to the 1930s, rickets, or severe childhood vitamin D deficiency, was epidemic in the United States and Europe, afflicting an estimated 85% of children in industrial cities. In the United States today, milk and infant formula are fortified with vitamin D and frank rickets is now uncommon. Despite these public health measures, recent research has found an extraordinarily high prevalence of vitamin D deficiency afflicting over half of certain elderly populations1 and an unexpected 30% of healthy young adults in Boston 2. A deeper understanding of vitamin D photobiology is changing our concept of what is “normal” as well as our national nutritional guidelines.
Vitamin D Biology
Vitamin D is the precursor of calcitriol (1,25-dihydroxyvitamin D), a hormone that has a number of important functions. Vitamin D is synthesized in the skin (after UV light exposure) or consumed, and then is stored until needed. When the serum concentration of vitamin D is below normal, both intestinal calcium and phosphorus absorption decrease. Calcitriol stimulates intestinal calcium absorption by interacting with the vitamin D receptor in the small intestine. The net effect is an enhancement of calcium entry through an epithelial calcium channel. Therefore, calcitriol’s major biologic activity on bone is indirect: to promote passive mineralization of the collagen matrix (osteoid) by maintaining extracellular calcium and phosphorus in a supersaturated state. Vitamin D is 25 hydroxylated in the liver in a largely unregulated step and activated to calcitriol by 25-hydroxyvitamin D-1-alpha hydroxylase in the kidney (tightly regulated). In the physiological state of calcium deficiency PTH levels rise resulting in Renal 1 hydroxylation of 25-hydroxyvitamin D and increased production of 1,25 hydroxyvitamin D. Calcitriol interacts with the vitamin D receptor on osteoblasts to generate RANKL on their surface membrane. Interaction with the RANK receptor on pre-osteoclasts induces maturation to fully mature osteoclasts that are essential for osteoclastic bone resorption with subsequent release of calcium into the extracellular space3.
One can get vitamin D in two ways: diet and from skin exposed to significant ultraviolet light. The main dietary sources of vitamin D are vitamin D fortified milk, margarine and cereal, although fish, liver and egg yolks are good but lesser sources. Sun exposure (specifically UVB light) is our predominant source of vitamin D via photo-conversion of vitamin D precursors to pre-vitamin D3 in skin. Depending on the latitude, 15-30 minutes of direct daily spring/summer/fall midday sun exposure is sufficient to provide all the vitamin D that we need. Considerable seasonal variation in vitamin D stores (and bone density) exists in people living north of 35oN – (North Carolina) and south of 35oS – (Buenos Aires). Populations living in these latitudes are more susceptible to vitamin D insufficiency. Furthermore, an elderly person over the age of 70 produces <30% of the vitamin D of a young person with the same sun exposure3. This, combined with less efficient vitamin D intestinal absorption, makes the elderly shut-in patient particularly susceptible to vitamin D deficiency. Significant amounts of vitamin D supplements must be supplied to overcome these effects.
Vitamin D Deficiency Defined
Assessment of vitamin D stores is best done by measurement of 25-hydroxyvitamin D. The definition of normal levels of 25-hydroxyvitamin D has changed in recent years as the effects of mild vitamin D deficiency have become known. Most commercial laboratories still use 9-15 ng/ml as the lower limit of normal for vitamin D. Although there is some controversy, optimal serum levels of 25-hydroxyvitamin D to avoid increases in PTH are at least 20 ng/ml4. Heany has suggested the appropriate serum 25-hydroxyvitamin D level is 32 ng/ml5,6,7. Although hypocalciuria (24 hour urine) may suggest vitamin D deficiency, patients with inadequate vitamin D stores often have normocalciuria.
Vitamin D Deficiency Prevalence
In a series of consecutive patients admitted to a Boston general medical service, 57% of the patients were found to be deficient in vitamin D (25-hydroxyvitamin D <15 ng/ml)1. In another study of predominantly medical workers in Boston, 30% of young adults were found to be deficient (<20 ng/ml)2 at the end of winter, while 11% were deficient at the end of summer. Bone density studies performed on patients at the end of winter were shown to be significantly diminished. This corresponds to the peak hip fracture time as well as the nadir 25-hydroxyvitamin D level 8. Perhaps most significantly, 50% of women admitted with a hip fracture in one Boston study had low 25-hydroxyvitamin D levels (<12 ng/ml)9.
Vitamin D Deficiency Clinical Importance
The clinical consequences of vitamin D deficiency include osteomalacia, increased susceptibility to fragility fractures, bone pain, and muscle weakness. Vitamin D deficiency should be suspected in patients who receive little or no direct sunlight (e.g., elderly shut-ins, people living in northern climates and individuals that engage in total solar protection using sunscreen), vitamin D deficient diets, and fat malabsorption syndromes (e.g., Crohn’s Disease, celiac disease, intestinal bypass surgery). Phenytoin, phenobarbital, cadmium, and rifampin are known to interfere with vitamin D metabolism. Cholestyramine inhibits vitamin D absorption. Less commonly, there are several known inherited and acquired disorders of metabolism of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D.
All of these conditions result in a state of secondary hyperparathyroidism. Secondary hyperparathyroidism is known to increase osteoclast activity and increase bone resorption that results in decreased bone density and increased risk of fragility fracture9.
There is a considerable body of evidence now suggesting that vitamin D deficiency contributes to increased risk for falling. Vitamin D deficiency has been associated with weaker quadriceps, slower reaction times, impaired postural stability, and slower functional performance in one controlled study of patients referred to a fall clinic10.
Treatment and Prevention of Vitamin D Deficiency
While there is no generally accepted treatment guideline for vitamin D deficiency, one commonly used strategy is vitamin D 50,000 units one to three times a week orally for eight weeks followed by 400 units daily. This has been shown to normalize PTH and vitamin D levels. Repeating these levels would be a prudent way to ensure treatment success4. A target point for vitamin D adequacy is above 30 ng/ml. One additional caveat is the considerable variability in serum vitamin D levels between laboratories11,14. Clearly, standardization of 25-hydroxyvitamin D measurements is essential. Given the high prevalence of vitamin D deficiency among young and old, increasing the public’s awareness and the development of prevention strategies become paramount. The combination of vitamin D and calcium supplementation has been shown to significantly reduce the incidence of non-vertebral and hip fractures in two large prospective double blind placebo controlled studies of elderly men and women8,12. In these studies and others, it has been difficult to separate out the effects of vitamin D from calcium supplementation. Of interest, a large British randomized double blind placebo controlled study (men and women age 65-85) reported the benefit of vitamin D 100,000 units every three months in reducing the incidence of any fracture 22% and any osteoporosis fracture 33%13. There was no separate calcium supplement. The treatment was well tolerated and inexpensive.
In summary, vitamin D deficiency is extremely prevalent among the elderly and is associated with a higher risk of fracture. Simple treatments with calcium and vitamin D have now been clearly demonstrated to reduce fracture risk and are well tolerated. The Food and Nutrition Board of the National Academy of Sciences established adequate daily vitamin D intake levels of 400 IU for those aged 51-69 and 600 IU for men and women over age 70. Most researchers currently feel that greater amounts of vitamin D are necessary, particularly during the winter in the northern latitudes. Additional studies will assist in clarifying the specific requirements for vitamin D supplementation.
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2. Tangpricha V et al, Vitamin D insufficiency among free-living healthy young adults. Am J Med 2002; 112:659-662
3. Holick MF, “Vitamin D: Photobiology, Metabolism, Mechanism of Action, and Clinical Applications” in Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism ed. Murray Favus. 4th edition 1999. Lippincott Williams & Wilkens.. Philadelphia, PA. pp. 92-98
4. Malabanan M et al, Redefining vitamin D insufficiency. Lancet 1998;351:805-806
5. Heany RP, Human serum 25-hydroxy-cholecalciferol response to extended oral dosing with cholecalciferol, Am J Clin Nutr, 77:204-210, 2003
6. Heany, RP, Calcium Absorption Varies within the Reference Range for Serum 25-Hydroxyvitamin D, Journal of the American College of Nutrition, 22, Nol 2, 142-146 (2003)
7. Chapuy, M.-C., Prevalence of Vitamin D Insufficiency in an Adult Normal Population, OI, 7:439-443, 1997
8. Dawson-Hughes B et al, Effect of calcium and Vitamin D supplementation on bone density in men and women 65 years of age or older. N Eng J Med 1997;337:670-676
9. LeBoff MS et al, Occult Vitamin D deficiency in postmenopausal US women with acute hip fracture. JAMA 1999;281:1505-1511
10. Dhesi JK et al, Neuromuscular and psychomotor function in elderly subjects who fall and the relationship with vitamin D status. J Bone Miner Res 2002;17:891
11. Binkley N et al, Assay variation confounds hypovitaminosis D diagnosis: a call for standardization. Presented ASBMR meeting. Minneapolis, MN. Sept. 2003; Abstract F482
12. Chapuy MC et al, Vitamin D3 and calcium to prevent hip fractures in elderly women. N Engl J Med 1992;327:1637-1642
13. Trivedi DP et al, Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. BMJ 2003;326:469
14. Lips P et al, An international comparison of serum 25-hydroxyvitamin D measurements. Osteoporos Int 1999;9: 394-397
Last modified: December 17, 2012