Schematic representation of the synthesis and metabolism of vitamin D for regulating calcium, phosphorus, and bone metabolism. During exposure to sunlight 7-dehydrocholesterol in the skin is converted to previtamin D3. Previtamin D₃ immediately converts by a heat dependent process to vitamin D₃. Exces-sive exposure to sunlight degrades previtamin D₃ and vitamin D₃ into inactive photoproducts. Vitamin D₂ and vitamin D₃ from dietary sources is incorporated into chylomicrons, transported by the lymphatic system into the venus circulation. Vitamin D (D represents D2 or D3) made in the skin or ingested in the diet can be stored in and then released from fat cells. Vitamin D in the circulation is bound to the vitamin D binding protein which transports it to the liver where vitamin D is converted by the vitamin D-25-hydroxylase to 25-hydroxyvitamin D [25(OH)D]. This is the major circulating form of vitamin D that is used by clinicians to measure vitamin D status (although most reference laboratories report the normal range to be 20-100 ng/mL, the preferred healthful range is 30-60 ng/mL). It is biologically inactive and must be converted in the kidneys by the 25-hy-droxyvitamin D-1α-hydroxylase (1-OHase) to its biologically active form 1,25-di-hydroxyvitamin D [1,25(OH)2 D]. Serum phosphorus, calcium fibroblast growth factors (FGF-23) and other factors can either increase (+) or decrease (-) the renal production of 1,25(OH)₂ D. A 1,25(OH)₂ D feedback regulates its own synthesis and decreases the synthesis and secretion of parathyroid hormone (PTH) in the parathyroid glands. A 1,25(OH)₂ D increases the expression of the 25-hy-droxyvitamin D-24-hydroxylase (24-OHase) to catabolize 1,25(OH)2 D to the wa-ter soluble biologically inactive calcitroic acid which is excreted in the bile. A 1,25(OH)₂ D enhances intestinal calcium absorption in the small intestine by stim-ulating the expression of the epithelial calcium channel (ECaC) and the calbin-din 9K (calcium binding protein, CaBP). A 1,25(OH)₂ D is recognized by its receptor in osteoblasts causing an increase in the expression of receptor activator of nuclear factor kappa B ligand (RANKL). Its receptor RANK on the preosteoclast binds RANKL which induces the preosteoclast to become a mature osteoclast. The mature osteoclast removes calcium and phosphorus from the bone to main-tain blood calcium and phosphorus levels. Adequate calcium and phosphorus levels promote the mineralization of the skeleton. Reprinted from Holick MF copyright 2007 with permission. 7-DHC, 7-dehydrocholesterol; UVB, ultraviolet B.

(A, B) Influence of season, time of day, and latitude on the synthesis of previtamin D3 in Northern hemispheres. (C, D) Influence of season, time of day, and latitude on the synthesis of previtamin D₃ in Southern hemispheres. The hour indicated in B and D is the end of the 1-hour exposure time. Reprinted from Holick MF copyright 1998 with permission.

Metabolism of 25-hydroxyvitamin D [25(OH)D] to 1,25 dihydroxyvitamin D 1,25(OH)2D for non-skeletal functions. When a monocyte/macrophage is stim-ulated through its toll-like receptor 2/1 (TLR2/1) by an infective agent such as Mycobacterium tuberculosis (TB), or its lipopolysaccharide (LPS) the signal up-regulates the expression of vitamin D receptor (VDR) and the 25-hydroxyvitamin D-1-hydroxylase (1-OHase). The 25(OH)D levels > 30 ng/mL provides adequate substrate for the 1-OHase to convert it to 1,25(OH)₂ D. A 1,25(OH)₂ D returns to the nucleus where it increases the expression of cathelicidin (CD) which is a peptide capable of promoting innate immunity and inducing the destruction of infective agents such as TB. It is also likely that the 1,25(OH)2 D produced in the monocytes/macrophage is released to act locally on activated T (AT) and activated B (AB) lymphocytes which regulate cytokine and immunoglobulin synthesis respectively. When 25(OH)D levels are ~30 ng/mL, it reduces risk of many common cancers. It is believed that the local production of 1,25(OH)2 D in the breast, colon, prostate, and other cells regulates a variety of genes that control proliferation including p21 and p27 as well as genes that inhibit angiogenesis and induced apoptosis. Once 1,25(OH)₂ D completes the task of maintaining normal cellular proliferation and differentiation, it induces the 25-hydroxyvita-min D-24-hydroxylase (24-OHase). The 24-OHase enhances the metabolism of 1,25(OH)2 D to calcitroic acid which is biologically inert. Thus, the local production of 1,25(OH)₂ D does not enter the circulation and has no influence on calcium metabolism. The parathyroid glands have 1-OHase activity and the local production of 1,25(OH)₂ D inhibits the expression and synthesis of PTH. The production of 1,25(OH)2 D in the kidney enters the circulation and is able to down regulate renin production in the kidney and to stimulate insulin secretion in the β-islet cells of the pancreas. Reprinted from Holick MF copyright 2007 with permission. BP, blood pressure; BS, blood sugar; PTH, parathyroid hormone; RXR, retinoic acid X receptor.

(A) Mean ± SE serum parathyroid hormone (PTH; picograms per milliliter) by serum 25-hydroxyvitamin D (25[OH]D) subgroups. Subject PTH concentrations (picograms per milliliter) relative to serum 25(OH)D concentrations sorted by subgroups delineated by predefined cutoffs for analyses of 25(OH)D inadequacy. Serum PTH values began to increase with 25(OH)D concentrations less than 29.8 ng/mL. (B) Percent of subjects with secondary hyperparathyroidism by 25(OH)D level. The percent of subjects with secondary hyperparathyroidism (PTH > 40 pg/mL) sorted by subgroups with serum 25(OH)D concentrations delineated by predefined cutoffs for analyses of 25(OH)D inadequacy. Reprinted from Holick MF et al. J Clin Endocrinol Metab 90:3215-3224, 2005 [39] with permission.

(A) Prevalence at risk of vitamin D deficiency defined as a 25-hy-droxyvitamin D < 12-20 ng/mL by age and sex: United States, 2001-2006. (B) Mean intake of vitamin D (international unit, IU) from food and food plus dietary supplements from Continuing Survey of Food Intakes by Individuals (CSFII) 1994-1996, 1998 and the Third National Health and Nutrition Examination Survey (NHANES III) 1988-1994. (C) Reported incidence of vitamin D deficiency defined as a 25-hydroxyvitamin D < 20 ng/mL around the globe including Australia (AU), Canada (CA), China (CH), India (IN), Korea (KR), Malaysia (MA), Middle East (ME), Mongolia (MO), New Zealand (NZ), North Africa (NA), Northern Europe (NE), and United States (US). Reprinted from Holick MF et al. J Clin Endocrinol Metab 97:1153-1158, 2012 [76] with permission.

Comparison of serum vitamin D₃ levels after a whole-body exposure (in a bathing suit; bikini for women) to 1 minimal erythemal dose (MED) of simulat-ed sunlight compared with a single oral dose of either 10,000 or 25,000 international unit (IU) of vitamin D₂. Reprinted from Holick MF copyright 1994 with permission.

A schematic representation of the major causes for vitamin D deficiency and potential health consequences. Reprinted from Holick MF copyright 2010 with permission. AODM, adult-onset diabetes mellitus; CHD, coronary heart disease; FEV1, forced expiratory volume in 1 second; HBP, high blood pressure; URI, upper respiatory infection; TB, tuberculosis; MS, multiple sclerosis; RA, rheumatoid arthritis.