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Biomedical subjects

Michael F Holick

Publications and source records attributed to Michael F Holick.

At least 55 records · Page 3Linked to original sources

Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis.

The purpose of this review is to put into perspective the many health benefits of vitamin D and the role of vitamin D deficiency in increasing the risk of many common and serious diseases, including some common cancers, type 1 diabetes, cardiovascular disease, and osteoporosis. Numerous epidemiologic studies suggest that exposure to sunlight, which enhances the production of vitamin D(3) in the skin, is important in preventing many chronic diseases. Because very few foods naturally contain vitamin D, sunlight supplies most of our vitamin D requirement. 25-Hydroxyvitamin D [25(OH)D] is the metabolite that should be measured in the blood to determine vitamin D status. Vitamin D deficiency is prevalent in infants who are solely breastfed and who do not receive vitamin D supplementation and in adults of all ages who have increased skin pigmentation or who always wear sun protection or limit their outdoor activities. Vitamin D deficiency is often misdiagnosed as fibromyalgia. A new dietary source of vitamin D is orange juice fortified with vitamin D. Studies in both human and animal models add strength to the hypothesis that the unrecognized epidemic of vitamin D deficiency worldwide is a contributing factor of many chronic debilitating diseases. Greater awareness of the insidious consequences of vitamin D deficiency is needed. Annual measurement of serum 25(OH)D is a reasonable approach to monitoring for vitamin D deficiency. The recommended adequate intakes for vitamin D are inadequate, and, in the absence of exposure to sunlight, a minimum of 1000 IU vitamin D/d is required to maintain a healthy concentration of 25(OH)D in the blood.

Breast Feeding↗

Tanning is associated with optimal vitamin D status (serum 25-hydroxyvitamin D concentration) and higher bone mineral density.

BACKGROUND: Vitamin D is made in the skin on exposure to solar radiation, and it is necessary to optimal skeletal health. Subjects who use a tanning bed that emits ultraviolet B radiation (290-315 nm) are likely to have higher 25-hydroxyvitamin D [25(OH)D] concentrations than do subjects who do not regularly use a tanning bed. OBJECTIVE: The first objective of this study was to ascertain whether subjects who regularly use a tanning bed have higher 25(OH)D concentrations than do subjects who do not use a tanning bed. The second objective was to ascertain whether higher 25(OH)D concentrations correlated positively with bone mineral density. DESIGN: This cross-sectional analysis examined 50 subjects who used a tanning bed at least once a week and 106 control subjects. Each subject gave a blood specimen for measurement of serum 25(OH)D and parathyroid hormone concentrations. Each subject underwent bone mineral density testing of the hip and spine. RESULTS: Subjects who used a tanning bed had serum 25(OH)D concentrations 90% higher than those of control subjects (115.5 +/- 8.0 and 60.3 +/- 3.0 nmol/L, respectively; P <0.001). Subjects who used a tanning bed had parathyroid hormone concentrations 18% lower than those of control subjects (21.4 +/- 1.0 and 25.3 +/- 0.8 pg/mL, respectively; P=0.01). Tanners had significantly higher BMD and z scores at the total hip than did nontanners. CONCLUSION: The regular use of a tanning bed that emits vitamin D-producing ultraviolet radiation is associated with higher 25(OH)D concentrations and thus may have a benefit for the skeleton.

Absorptiometry, Photon↗

Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease.

Most humans depend on sun exposure to satisfy their requirements for vitamin D. Solar ultraviolet B photons are absorbed by 7-dehydrocholesterol in the skin, leading to its transformation to previtamin D3, which is rapidly converted to vitamin D3. Season, latitude, time of day, skin pigmentation, aging, sunscreen use, and glass all influence the cutaneous production of vitamin D3. Once formed, vitamin D3 is metabolized in the liver to 25-hydroxyvitamin D3 and then in the kidney to its biologically active form, 1,25-dihydroxyvitamin D3. Vitamin D deficiency is an unrecognized epidemic among both children and adults in the United States. Vitamin D deficiency not only causes rickets among children but also precipitates and exacerbates osteoporosis among adults and causes the painful bone disease osteomalacia. Vitamin D deficiency has been associated with increased risks of deadly cancers, cardiovascular disease, multiple sclerosis, rheumatoid arthritis, and type 1 diabetes mellitus. Maintaining blood concentrations of 25-hydroxyvitamin D above 80 nmol/L (approximately 30 ng/mL) not only is important for maximizing intestinal calcium absorption but also may be important for providing the extrarenal 1alpha-hydroxylase that is present in most tissues to produce 1,25-dihydroxyvitamin D3. Although chronic excessive exposure to sunlight increases the risk of nonmelanoma skin cancer, the avoidance of all direct sun exposure increases the risk of vitamin D deficiency, which can have serious consequences. Monitoring serum 25-hydroxyvitamin D concentrations yearly should help reveal vitamin D deficiencies. Sensible sun exposure (usually 5-10 min of exposure of the arms and legs or the hands, arms, and face, 2 or 3 times per week) and increased dietary and supplemental vitamin D intakes are reasonable approaches to guarantee vitamin D sufficiency.

Adolescent↗

Analysis of the vitamin D system in cutaneous squamous cell carcinomas.

BACKGROUND: Increasing evidence points at an important function of vitamin D metabolites for growth regulation in various tissues, and new vitamin D analogs are interesting candidates for the treatment of malignancies, including squamous cell carcinomas (SCC). METHODS: We have analyzed expression of vitamin D receptor (VDR), vitamin D-25-hydroxylase (25-OHase), 25-hydroxyvitamin D-1 alpha-hydroxylase (1 alpha-OHase), and 1,25-dihydroxyvitamin D-24-hydroxylase (24-OHase) in SCC. RESULTS: Intensity of VDR immunoreactivity was increased in SCCs as compared to normal human skin. VDR staining did not correlate with histological type or grading, nor with markers for proliferation, differentiation, or apoptotic cells. Incubation of SCC cell lines (SCL-1, SCL-2) with calcitriol resulted in a dose-dependent suppression of cell proliferation (approximately up to 30%) in vitro, as measured by a tetrazolium salt (WST-1)-based colorimetric assay. RNA levels for VDR, 25-OHase, 1 alpha-OHase, and 24-OHase were significantly elevated in SCCs as compared to HS, as measured by real-time polymerase chain reaction. CONCLUSIONS: Our findings demonstrate that modulation of VDR expression and local synthesis or metabolism of vitamin D metabolites may be of importance for growth regulation of SCCs. Additionally, SCCs represent potential targets for therapy with new vitamin D analogs that exert little calcemic side effects or for pharmacological modulation of calcitriol synthesis/metabolism in these tumors.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗

Testosterone increases bone mineral density in female-to-male transsexuals: a case series of 15 subjects.

OBJECTIVE: Testosterone therapy for osteoporosis has not been studied extensively in women because of its potential to cause virilization. Female-to-male transsexuals are genetic females who suffer from gender dysphoria and thus take supra-physiologic doses of testosterone to change from the female to male phenotype. The aim of this study is to examine the effects of testosterone treatment on the genetic female skeleton. PATIENTS AND DESIGN: A group of 15 female-to-male transsexuals was prospectively enrolled for observation over a 2-year period. The subjects had a mean age of 37.0 +/- 3.0 years. All of the subjects self-administered testosterone esters intramuscularly at a mean dose of 70.7 +/- 4.5 mg weekly. MEASUREMENTS: The subjects had measurements of bone mineral density (BMD) by dual X-ray absorptiometry (DXA) of the femoral neck and spine (L2-L4) at 12-month intervals. They had determinations of serum oestradiol, testosterone, soluble RANKL (sRANKL), osteoprotegerin (OPG) and urine N-telopeptide (NTX) at the date of enrolment and at the end of 2 years. results There was a significant positive increase in mean BMD of 7.8% at the femoral neck and a nonsignificant increase in mean BMD of 3.1% at the spine over 2 years. The levels of testosterone reached the upper normal range for males and the levels of oestradiol declined to near the postmenopausal range. sRANKL levels decreased significantly in female-to-male transsexuals who newly initiated testosterone therapy. There was no significant change in urine NTX or serum OPG during the study. CONCLUSIONS: We conclude that supra-physiologic testosterone therapy increases BMD at the hip while maintaining BMD at the spine in female-to-male transsexuals. The effects of testosterone may be the result of testosterone hormone directly acting on the bone or indirectly through aromatization to oestradiol. Lower RANKL levels coupled with unchanged OPG levels results in an increased OPG/RANKL ratio, which may be beneficial to the bone by inhibiting osteoclastogenesis.

Absorptiometry, Photon↗

Vitamin D: A millenium perspective.

Vitamin D is one of the oldest hormones that have been made in the earliest life forms for over 750 million years. Phytoplankton, zooplankton, and most plants and animals that are exposed to sunlight have the capacity to make vitamin D. Vitamin D is critically important for the development, growth, and maintenance of a healthy skeleton from birth until death. The major function of vitamin D is to maintain calcium homeostasis. It accomplishes this by increasing the efficiency of the intestine to absorb dietary calcium. When there is inadequate calcium in the diet to satisfy the body's calcium requirement, vitamin D communicates to the osteoblasts that signal osteoclast precursors to mature and dissolve the calcium stored in the bone. Vitamin D is metabolized in the liver and then in the kidney to 1,25-dihydroxyvitamin D [1,25(OH)(2)D]. 1,25(OH)(2)D receptors (VDR) are present not only in the intestine and bone, but in a wide variety of other tissues, including the brain, heart, stomach, pancreas, activated T and B lymphocytes, skin, gonads, etc. 1,25(OH)(2)D is one of the most potent substances to inhibit proliferation of both normal and hyperproliferative cells and induce them to mature. It is also recognized that a wide variety of tissues, including colon, prostate, breast, and skin have the enzymatic machinery to produce 1,25(OH)(2)D. 1,25(OH)(2)D and its analogs have been developed for treating the hyperproliferative disease psoriasis. Vitamin D deficiency is a major unrecognized health problem. Not only does it cause rickets in children, osteomalacia and osteoporosis in adults, but may have long lasting effects. 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. There needs to be a better appreciation of the importance of vitamin D for overall health and well being.

Adult↗

Prostatic 25-hydroxyvitamin D-1alpha-hydroxylase and its implication in prostate cancer.

Evidence suggests that vitamin D may have a protective role for prostate cancer. 1alpha,25-Dihydroxyvitamin D [1alpha,25(OH)(2)D] inhibits growth and induces differentiation of prostate cells. 25-Hydroxyvitamin D-1alpha-hydroxylase [1alpha-OHase], the enzyme that is responsible for the synthesis of 1alpha,25(OH)(2)D, is expressed in cultured prostate cells. We observed a marked decrease in 1alpha-OHase activity in prostate cancer cells, suggesting some defect of the 1alpha-OHase in these cells. To investigate whether the defect was due to dysregulation of the enzyme at the promoter level, a series of deletion constructs of the promoter was synthesized and incorporated upstream into the luciferase reporter gene. Two regions were identified with high basal activity in transfected normal prostate cell line (PZHPV-7), -1100 bp (AN2), and -394 bp (AN5) upstream of ATG start site of the 1alpha-OHase gene. When the reporter gene with either AN2 or AN5 was transfected into prostate cancer cell lines, we observed a lower basal promoter activity in PC-3 cells and DU145 cells than that found in PZHPV-7 cells for both constructs, and a loss of promoter activity in LNCaP cells. Thus, the results suggest that the defect in enzyme activity may result from the decreased promoter activity in prostate cancer cells.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗

Evolution and function of vitamin D.

It is remarkable that phytoplankton and zooplankton have been producing vitamin D for more than 500 million years. The role of vitamin D in lower non-vertebrate life forms is not well understood. However, it is critically important that most vertebrates obtain an adequate source of vitamin D, either from exposure to sunlight or from their diet, in order to develop and maintain a healthy mineralized skeleton. Vitamin D deficiency is an unrecognized epidemic in most adults who are not exposed to adequate sunlight. This can precipitate and exacerbate osteoporosis and cause the painful bone disease osteomalacia. Once vitamin D is absorbed from the diet or made in the skin by the action of sunlight, it is metabolized in the liver to 25-hydroxyvitamin D [25(OH)D] and then in the kidney to 1,25-dihydroxyvitamin D [1,25(OH)2D]. 1,25(OH)2D interacts with its nuclear receptor (VDR) in the intestine and bone in order to maintain calcium homeostasis. The VDR is also present in a wide variety of other tissues. 1,25(OH)2D interacts with these receptors to have a multitude of important physiological effects. In addition, it is now recognized that many tissues, including colon, breast and prostate, have the enzymatic machinery to produce 1,25(OH)2D. The insights into the new biological functions of 1,25(OH)2D in regulating cell growth, modulating the immune system and modulating the renin-angiotensin system provides an explanation for why diminished sun exposure at higher latitudes is associated with increased risk of dying of many common cancers, developing type 1 diabetes and multiple sclerosis, and having a higher incidence of hypertension. Another calciotropic hormone that is also produced in the skin, parathyroid hormone-related peptide, is also a potent inhibitor of squamous cell proliferation. The use of agonists and antagonists for PTHrP has important clinical applications for the prevention and treatment of skin diseases and disorders of hair growth.

Animals↗

Regulation of the 25-hydroxyvitamin D-1alpha-hydroxylase gene and its splice variant.

The 25-hydroxyvitamin D-1alpha-OHase (1alpha-OHase) is responsible for producing the active form of vitamin D, 1alpha,25-dihydroxyvitamin D. The enzyme not only is expressed in kidneys, but also is expressed in many nonrenal tissues, including skin. In this study, we compared the regulation of the 1alpha-OHase expression in kidney cells and keratinocytes. Using transfected luciferase reporter gene constructs, we compared the activity and regulatory features of the human 1alpha-OHase gene promoter in C-21 human kidney cells (PTH/PTHrP receptor positive) and cultured human keratinocytes (NHKs). We found that two regions, -1,100 bp and -396 bp from the ATG, were highly sensitive to parathyroid hormone (PTH) in C-21 cells but not in NHK. Furthermore, three CRE-like sequences (CLS) were identified within this PTH-sensitive area of the 1alpha-OHase promoter and when deleted they reduced induction of PTH by 50%-95% in C-21 cells. To further investigate the differential regulation profile, we examined the protein products of 1alpha-OHase in kidney and skin. Western blot analysis of whole cell extracts from these tissues with a 1alpha-OHase-specific antibody revealed the predicted 1alpha-OHase protein product of 56 kDa in kidney and a larger protein product of 59 kDa in skin. Using RT-PCR for the 1alpha-OHase in skin and kidney, we detected an insertion between exons 2 and 3 in skin but not in kidney. These results suggest that the regulation of renal and skin 1alpha-OHase gene expression may be tissue specific and possibly produce different splice variants, and that this specificity is likely conferred by differential expression of CRE-binding proteins in different cell types. In conclusion, the differential tissue expression of 1alpha-OHase gene variants and the tissue-specific regulation profile open up a new paradigm in the understanding of the role of 25-hydroxyvitamin D3 1alpha-hydroxylase gene in the regulation of vitamin D physiology.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗

Vitamin D autocrine system and prostate cancer.

25-Hydroxyvitamin D-1alpha-hydroxylase (lalpha-OHase) is expressed in prostate cells. The expression suggests that local production of 1,25-dihydroxyvitamin D could provide an important cell growth regulatory mechanism. However, there is differential expression of 1alpha-OHase activity among the primary cultures of prostate cells derived from cancerous, benign prostatic hypertrophy and normal tissue, and among noncancerous (PZHPV-7) and various cancer cell lines (PC-3, DU145). No activity was found in cancer cell line LNCaP. The observed marked decrease in 1alpha-OHase activity in prostate cancer cells suggests some defect of the 1alpha-OHase in these cells. Using luciferase reporter gene assay, we observed a step-wise decrease in the basal promoter activity in two truncated promoter fragments, AN2 (-1,100 bp) and AN5 (-394 bp), with the highest basal activities found in PZHPV-7 and with loss of promoter activity in LNCaP. In order to understand the mechanism underlying the differential promoter activities among different prostate cells, we investigated the possible role of phosphorylation of cyclic AMP response element binding protein (CREB) on the regulation of 1alpha-OHase promoter activity in the four prostate cell lines. First we compared the levels of CREB phosphorylation among PZHPV-7, DU145, PC-3 and LNCaP cells by Western blot analysis using antibody against phosphorylated CREB. We observed that CREB was phosphorylated to a greater extent in PZHPV-7 than in DU145 cells. No significant phosphorylation of CREB was found in PC-3 and LNCaP cells. Next, we utilized activators and inhibitors of protein kinase A (PKA), protein kinase C (PKC), mitogen-activated protein kinase kinase (MAPKK) and calcium/calmodulin-dependent protein kinase II (CaMKII) to determine which kinases might be involved in phosphorylating the CREB in PZHPV-7 cells. We demonstrated that forskolin (an activator of PKA) increased the AN2 basal promoter activity 50%, whereas H-89 (an inhibitor of PKA) inhibited the basal and forskolin-stimulated AN2 promoter activity 40% and 70%, respectively. We also showed that PD98059 (an inhibitor of MAPKK) decreased the AN2 promoter activity 70%. Phorbol 12-myristate 13-acetate (an activator of PKC), GF109203 (an inhibitor of PKC) and KN-93 (an inhibitor of CaMKII) had no effect on AN2 promoter activity in PZHPV-7 cells. Thus, our results suggest that differential phosphorylation of CREB through PKA and MAPK pathways may be involved in the regulation of 1alpha-OHase promoter activity.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗

Analysis of the vitamin D system in cutaneous malignancies.

1,25-dihydroxyvitamin D3, the biological active metabolite of vitamin D, has great impact on keratinocyte growth and differentiation, and consequently has already been successfully used in the therapy of hyperproliferative skin disorders. We have now characterized the key components of the vitamin D system (VDR, 1alpha-OHase, 24-OHase and 25-OHase) in cutaneous basal cell carcinomas (BCC) and squamous cell carcinomas (SCC), using immunohistochemical and quantitative real-time PCR techniques. Additionally, proliferative activity (Ki-67 expression), differentiation status (cytokeratin 10 and transglutaminase K expression), rate of apoptosis (TUNEL assay) and the abundance of the main heterodimerization partners of VDR (RXRs) was determined for these tumours and correlated with the components of the Vitamin D system. Our findings indicate that the Vitamin D system may be of high importance for the growth behaviour of BCCs and SCCs and that new vitamin D analogues that exert less calcaemic side effects may be effective in the prevention or treatment of these tumours.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗

Evaluation of vitamin D analogs as therapeutic agents for prostate cancer.

Prostate cancer cells contain specific receptors (VDR) for la,25-dihydroxyvitamin D (1alpha,25(OH)2D), which is known to inhibit the proliferation and invasiveness of these cells. These findings support the use of 1alph,25(OH)2D for prostate cancer therapy. However, because 1alpha,25(OH)2D can cause hypercalcemia, analogs of 1alpha,25(OH)2D that are less calcemic but which exhibit potent antiproliferative activity would be attractive as therapeutic agents. We studied four vitamin D compounds: 25-hydroxyvitaminD3 [25(OH)D3], which is converted to 1alpha,25(OH)2D3 in prostate cells, and three analogs of 1alpha,25(OH)2D3: EB1089, 19-nor-1alpha,25(OH)2D2 and hexafluoro-1alpha,25(OH)2D3 (F6-1alpha,25(OH)2D3). 19-nor-1alpha,25(OH)2D2 has been shown to be less calcemic than 1alpha,25(OH)2D3 in clinical trials. F6-1alpha,25(OH)2D3 has been shown to be 100-fold more active than 1alpha,25(OH)2D3 and to be longer-lasting in inhibiting keratinocyte proliferation in vitro. EB1089 has been shown to be less calcemic than 1alpha,25(OH)2D3 in rats implanted with Leydig cell tumors. For 25(OH)D3, 19-nor-1alpha,25(OH)2D2 and F6-1alpha,25(OH)2D3, we studied the in vitro effects and compared their activity to 1alpha,25(OH)2D3 on cellular proliferation by 3H-thymidine incorporation assay. In addition, we studied transactivation of the VDR in the presence of 25(OH)D3 and 19-nor-1alpha,25(OH)2D2 in prostate cells. For EB1089, we compared its inhibition of prostate cancer metastasis to that induced by 1alpha,25(OH)2D3 in vivo in the rat Dunning MAT LyLu prostate cancer model. We found that 1alpha,25(OH)2D3 and 19-nor-1alpha,25(OH)2D2 caused similar dose-dependent inhibition in 3H-thymidine incorporation into DNA in prostate cells and behaved similarly in the CAT reporter gene transactivation assay in PC-3/VDR cells. F6-1alpha,25(OH)2D3 is 10- to 50-fold more active than 1alpha,25(OH)2D3 in 3H-thymidine incorporation into DNA in the primary cultured prostate cells. Likewise, 25(OH)D3 had comparable antiproliferative activity to la,25(OH)2D3. In the rat model, tumor volumes and the number of metastases in the lungs were significantly reduced by both 1alpha,25(OH)2D3 (10.4 +/- 2.81 tumor foci) and EB1089 (7.7+/-1.29 tumor foci) compared to controls (22.7 +/- 1.98 tumor foci). Although serum calcium levels were significantly elevated in both 1alph,25(OH)2D3- and EB1089-treated rats, EB1089 was significantly less calcemic than 1alpha,25(OH)2D3 (12.59+/-0.21 mg/dl versus 14.47+/-.46 mg/dL; 1 microg/kg; p < 0.001). In conclusion, our data indicate that 25(OH)D3 and the three 1alpha,25(OH)2D analogs represent two different solutions to the problem of hypercalcemia associated with vitamin D-based prostate cancer therapies: 25(OH)D3 requires the presence of 25-hydroxyvitaminD-1alpha-hydroxylase, whereas 19-nor-1alpha,25(OH)2D2, F6-1alpha,25(OH)2D3 and EB1089 do not. These compounds may be good candidates for human clinical trials in prostate cancer.

Animals↗

Vitamin D and prostate cancer prevention and treatment.

Human prostate cells contain receptors for 1alpha,25-dihydroxyvitamin D, the active form of vitamin D. Prostate cancer cells respond to vitamin D(3) with increases in differentiation and apoptosis, and decreases in proliferation, invasiveness and metastasis. These findings strongly support the use of vitamin D-based therapies for prostate cancer and/or as a second-line therapy if androgen deprivation fails. The association between either decreased sun exposure or vitamin D deficiency and the increased risk of prostate cancer at an earlier age, and with a more aggressive progression, indicates that adequate vitamin D nutrition should be a priority for men of all ages. Here we summarize recent advances in epidemiological and biochemical studies of the endocrine and autocrine systems associated with vitamin D and their implications for prostate cancer and in the evaluation of vitamin D(3) and its analogs in preventing and/or treating prostate cancer.

Cholecalciferol↗

Thyroid hormone action on skin: diverging effects of topical versus intraperitoneal administration.

Previously, we demonstrated stimulation of epidermal proliferation and hair growth in triiodothyronine (T(3)) treated mice. To distinguish skin effects of directly applied T(3) from those of systemic hyperthyroidism, we treated CD-1 mice with either intraperitoneally (IP) or topically administered T(3). Relative to controls, mice receiving T(3) IP had 10% thinner epidermis (p < 0.01) and 48% fewer hairs (p < 0.001). By contrast, mice receiving T(3) topically had 78% thicker epidermis (p < 0.01) and 160% more hairs (p < 0.01). To gain insight into factors responsible for the diverging effects, we contrasted T(3) effect on proliferation of isolated keratinocyte cultures versus keratinocytes cocultured with dermal fibroblasts. For keratinocytes grown in the absence of fibroblasts, T(3) stimulated proliferation in a dose-dependent, biphasic pattern with the peak at 0.5 nM T(3) (84 +/- 30%, p < 0.05). Paradoxically, T(3) inhibited proliferation of keratinocytes cocultured with fibroblasts, the nadir at 0.1 nM T(3) (34% +/- 4%, p < 0.001). These studies are the first describing divergent effects of IP and topically administered thyroid hormone. The data suggest that while T(3) stimulated keratinocyte proliferation, T(3) also stimulated proliferation inhibitory factor(s) from skin fibroblasts. Insight into the interplay among the competing factors will be important in understanding thyroid hormone regulation of skin physiology.

Administration, Topical↗

Vitamin D and bone health in postmenopausal women.

Osteoporosis, a disease of increased skeletal fragility, is becoming increasingly common as the U.S. population ages. Adequate vitamin D and calcium intake is the cornerstone of osteoporosis prevention and treatment. Age-related changes in vitamin D and calcium metabolism increase the risk of vitamin D insufficiency and secondary hyperparathyroidism. Although longitudinal data have suggested a role of vitamin D intake in modulating bone loss in perimenopausal women, studies of vitamin D and calcium supplementation have failed to support a significant effect of vitamin D and calcium during early menopause. There is a clearer benefit in vitamin D and calcium supplementation in older postmenopausal women. Vitamin D intake between 500 and 800 IU daily, with or without calcium supplementation, has been shown to increase bone mineral density (BMD) in women with a mean age of approximately 63 years. In women older than 65, there is even more benefit with vitamin D intakes of between 800 and 900 IU daily and 1200-1300 mg of calcium daily, with increased bone density, decreased bone turnover, and decreased nonvertebral fractures. The decreases in nonvertebral fractures may also be influenced by vitamin D-mediated decreases in body sway and fall risk. There are insufficient available data supporting a benefit from vitamin D supplementation alone, without calcium, to prevent osteoporotic fracture in postmenopausal women.

Age Factors↗

Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol.

BACKGROUND: The cholecalciferol inputs required to achieve or maintain any given serum 25-hydroxycholecalciferol concentration are not known, particularly within ranges comparable to the probable physiologic supply of the vitamin. OBJECTIVES: The objectives were to establish the quantitative relation between steady state cholecalciferol input and the resulting serum 25-hydroxycholecalciferol concentration and to estimate the proportion of the daily requirement during winter that is met by cholecalciferol reserves in body tissue stores. DESIGN: Cholecalciferol was administered daily in controlled oral doses labeled at 0, 25, 125, and 250 micro g cholecalciferol for approximately 20 wk during the winter to 67 men living in Omaha (41.2 degrees N latitude). The time course of serum 25-hydroxycholecalciferol concentration was measured at intervals over the course of treatment. RESULTS: From a mean baseline value of 70.3 nmol/L, equilibrium concentrations of serum 25-hydroxycholecalciferol changed during the winter months in direct proportion to the dose, with a slope of approximately 0.70 nmol/L for each additional 1 micro g cholecalciferol input. The calculated oral input required to sustain the serum 25-hydroxycholecalciferol concentration present before the study (ie, in the autumn) was 12.5 micro g (500 IU)/d, whereas the total amount from all sources (supplement, food, tissue stores) needed to sustain the starting 25-hydroxycholecalciferol concentration was estimated at approximately 96 micro g (approximately 3800 IU)/d. By difference, the tissue stores provided approximately 78-82 micro g/d. CONCLUSIONS: Healthy men seem to use 3000-5000 IU cholecalciferol/d, apparently meeting > 80% of their winter cholecalciferol need with cutaneously synthesized accumulations from solar sources during the preceding summer months. Current recommended vitamin D inputs are inadequate to maintain serum 25-hydroxycholecalciferol concentration in the absence of substantial cutaneous production of vitamin D.

Administration, Oral↗

Fortification of orange juice with vitamin D: a novel approach for enhancing vitamin D nutritional health.

BACKGROUND: Fortification of milk with vitamin D may not be adequate for satisfying the vitamin D requirement because of variability in vitamin D content after fortification and because many persons have milk allergy or lactose intolerance. Additional foods need to be fortified with vitamin D. OBJECTIVE: We determined whether vitamin D, a fat-soluble vitamin, is bioavailable in orange juice and skim milk, 2 nonfat beverages. DESIGN: On 3 separate occasions, 18 adults ingested 25 000 IU vitamin D(2) in 240 mL whole milk or skim milk or in 0.1 mL corn oil applied to toast. A separate, double-blind, randomized, controlled trial investigated whether the consumption of orange juice fortified with vitamin D(3) would increase serum 25-hydroxyvitamin D [25(OH)D] concentrations: 14 subjects ingested 240 mL orange juice fortified with 1000 IU vitamin D, and 12 subjects ingested a control orange juice daily for 12 wk. RESULTS: Peak serum vitamin D(2) concentrations did not differ significantly after the ingestion of vitamin D(2) in whole milk, skim milk, or corn oil on toast. After subjects consumed orange juice fortified with 1000 IU vitamin D(3) daily for 12 wk, serum 25(OH)D(3) concentrations increased by 150%, and serum parathyroid hormone concentrations decreased by 25% compared with baseline; control subjects had a seasonal increase of 45% in 25(OH)D and no significant change in serum parathyroid hormone. CONCLUSIONS: The fat content of milk does not affect vitamin D bioavailability. Vitamin D fortification at 1000 IU/240 mL orange juice for 12 wk safely increased 25(OH)D(3) concentrations in adults.

Adult↗