Vitamin D Insufficiency, Deficiency, and Bone Health

There has been increasing interest in the potential benefits of vitamin D. Much of the stimulus came from meta-analysis of vitamin D and calcium in osteoporotic fracture studies as well as association studies relating increased prevalence of diseases such as cancer, diabetes, multiple sclerosis, and cardiovascular events with lower levels of serum 25-hydroxyvitamin D (25OHD). Vitamin D from diet or sun is converted in the liver to 25OHD and then in the kidney to 1,25-dihydroxyvitamin D 1,25(OH)2D, the active form of vitamin D. Normally, the main source of 1,25(OH)2D is the kidney, and serum 1,25(OH)2D is regulated by changes in serum calcium, phosphorus, fibroblast growth factor-23, and PTH; serum levels are held constant through homeostatic regulation. Circulating 1,25(OH)2D binds to the target tissues in the body that have a vitamin D receptor where it expresses vitamin D-responsive genes. In addition, many tissues (for example, breast, colon, prostate, bone, and immune cells) express 25OHD-1hydroxylase that converts 25OHD to 1,25-dihydroxyvitamin D locally. These local effects cause decreased proliferation of cells, increased cell differentiation, and cell survival. The importance of the peripheral conversion of 25OHD to 1,25(OH)2D relative to systemic production is difficult to assess, and nothing is known about the level of serum25OHDwhenperipheralconversionmightbe impaired. It is difficult to define adequate vitamin D nutrition because circulating vitamin D is derived from both dietary sources and sunlight; however, serum 25OHD is stable over weeks and serves as a biomarker of the adequacy of vitamin D supplies. The sunlight effect depends on distance from the equator, so for example in northern countries at 40° latitude, sunlight–or rather UVB radiation–is effective in converting 7-dehydrocholesterol to vitamin D3 in skin for about 7 months of the year and in Sweden at 55–65° latitude, monthly exposure to UVB is 5 months. The length of effective UVB exposure depends on the angle of the sun and atmospheric pollution, and the sun needs to be above 35° to be effective. With the ready availability of accurate serum 25OHD measurements, results from different countries show a lot of variation in levels, and the discussion centers on the significance of the values. What is a low level? In the past, vitamin D deficiency was defined as serum 25OHD below 10 ng/ml because both serum 1,25(OH)2D and calcium absorption declined significantly at this level (1, 2). The World Health Organization (WHO) defined vitamin D insufficiency as serum 25OHD below 20 ng/ml (50 nmol/ liter) (3). However, others recently started to define vitamin D deficiency as serum 25OHD level below 20 ng/ml and vitamin D insufficiency as less than 30 ng/ml (75 nmol/ liter) (4). The primary argument for this change in definition is based on the finding that serum PTH, which is inversely related to serum 25OHD, decreases as serum 25OHD increases and reaches a plateau at a serum 25OHD of approximately 30 ng/ml (75 nmol/liter). This is certainly controversial because numerous studies show a large variation in the plateau level of PTH ranging from a serum 25OHD of 18 ng/ml (45 nmol/liter) (5) to 30 ng/ml (75 nmol/liter) (6). This change in definition of vitamin D insufficiency actually has major significance because the dose of vitamin D required to increase people to a minimum serum 25OHD of 20 ng/ml (50 nmol/liter) is approximately 800 IU daily (7), whereas increasing people to a minimum level of 30 ng/ml (75 nmol/liter) would require approximately 4,000 IU daily (8). Unfortunately, there are no long-term prospective studies of either the efficacy or safety of these larger doses of vitamin D. There are two important questions: what data support recommending a minimum serum 25OHD level of either 20 ng/ml (50 nmol/liter) or 30