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The role of vitamin d in the prevention and treatment of osteoporosis

Clinical Reviews in Bone and Mineral Metabolism, vol. 2, no. 4, 373–388, Winter 2004 Copyright 2004 by Humana Press Inc. All rights of any nature whatsoever reserved. 1534-8644/04/4:373–388/$25.00 The Role of Vitamin D in the Prevention and Treatment
of Osteoporosis
Mary E. Elliott,
1
2
PharmD, PhD and Nicole M. Nolan, PharmD
1School of Pharmacy, University of Wisconsin-Madison, Madison, WI, and 2Massachusetts College of Abstract
Vitamin D is essential for preventing and treating osteoporosis. Vitamin D enhances intestinal calcium absorption to help maintain blood calcium concentrations, necessary for bone mineralization and for muscleand nerve function. Vitamin D is metabolized to 25-hydroxyvitamin D (25OHD) in the liver and to the activeform, 1,25-dihydroxyvitamin D [1,25(OH)2D] in the kidney. Inadequate vitamin D status contributes toincreased bone turnover, secondary hyperparathyroidism, bone loss, fractures, muscle weakness, osteomala-cia, and rickets in children.
Vitamin D is synthesized in the skin upon exposure to sunlight. It is also found naturally in some foods and is present in fortified foods, in nonprescription supplements containing other vitamins or calcium, and as purevitamin D in prescription and nonprescription forms.
The concept of vitamin D adequacy has evolved well beyond the need for vitamin D for preventing rick- ets. Recommendations for vitamin D intake were increased in 1997 but continue to be debated. The best mea-sure of vitamin D status is serum 25OHD, and recent studies suggest this should be at least 32 ng/mL. Manypeople fall short of this. Risks for poor vitamin D status include advanced age, minimal sun exposure, mal-absorption, and darkly pigmented skin. However, recent work suggests that many otherwise healthy individu-als are inadequate in vitamin D.
Although best known for its role in skeletal health, other roles for vitamin D in cancer, immunologic dis- ease, and other aspects of health are being explored. Greater understanding of its role in skeletal health andoverall well-being, and better avenues for assuring vitamin D adequacy for all people, are needed.
Key Words: Vitamin D; calcitriol; vitamin D receptor; calcium; osteoporosis; osteomalacia; sunlight.
Introduction
amin D—1,25-dihydroxyvitamin D [1,25(OH)2D]—is to maintain serum calcium within the normal Vitamin D and calcium are essential for the pre- range to allow for mineralization of bone and for vention and treatment of osteoporosis. The most normal muscle and nerve function. With inadequate important role of the biologically active form of vit- vitamin D and calcium, parathyroid hormone (PTH)concentrations are elevated, leading to increasedbone turnover, bone loss, and ultimately, to osteo- Address correspondence to Mary E. Elliott, PharmD, PhD, School of Pharmacy, University of Wisconsin-Madison, 777 The term vitamin D, without a subscript, refers to (cholecalciferol). Both are secosteroids and are fat- made. In northern and southern latitudes above 38° , soluble vitamins, but they differ slightly in their side little or no vitamin D3 synthesis occurs in winter, chains (3). Vitamins D2 and D3 are derived from dif- because of the angle at which the winter sun strikes ferent sources, but share many features and have the earth. With the longer distance that light travels similar biological effects in humans.
through earth’s atmosphere, light of shorter wave- Historically, consideration of vitamin D adequacy length (such as UV) is disproportionately scattered was based on prevention of rickets. Later, vitamin D (2,12). From November through February, even pro- adequacy was based on the concentration of the major longed exposure on a sunny day in Boston will not circulating form, 25-hydroxyvitamin D (25OHD), produce significant vitamin D (13). Wintertime with deficiency defined as being less than 10 ng/mL decreases in serum 25OHD are associated with and insufficiency between 10 and 20 ng/mL (4–6).
increased PTH, increased bone turnover, and reduced Debate continues regarding the optimum serum con- bone mineral density (BMD) (14).
centration of 25OHD, but recent studies suggest that In the warmer months in temperate climates, and serum 25OHD should be at least 32 ng/mL (7,8).
in warmer climates year-round, casual sun exposurecan provide adequate vitamin D. Suberythemal Photobiology of Vitamin D
exposure (25% of that needed to pinken the skin) ofhands, arms, and face two to three times a week is Vitamin D3 is produced in sunlit skin from its pre- reasonable. For healthy adults, approx 85% of their cursor 7-dehydrocholesterol (provitamin D) (3). This vitamin D stores come from sun exposure (1). For compound is plentiful in the dermis and epidermis sun worshippers, hypervitaminosis D is not a con- owing to the presence of an inhibitor of the enzyme cern, as the skin has built-in protective mechanisms 7-dehydrocholesterol reductase, which would other- (9). Cutaneous previtamin D, and vitamin D3 itself, wise convert the precursor to cholesterol. On expo- are converted to the inactive compounds lumisterol sure to ultraviolet B rays (UVB, 290–315 nm), and tachysterol, and suprasterol, respectively when provitamin D undergoes photolysis to previtamin D3.
This molecule is isomerized in a thermal, nonenzy-matic reaction, to vitamin D3, taking approx 10 h.
Vitamin D From Food
This step brings about an important conformational and Supplements
change, with the product vitamin D3 then being ableto leave the keratinocytes in the skin and pass into Vitamin D can be obtained from dietary sources dermal capillaries and into the bloodstream.
(Table 1). Natural food sources contain vitamin D3.
Production of vitamin D3 varies with the cuta- Many foods are supplemented with either vitamin D3 neous concentration of provitamin D, skin pigmenta- or with vitamin D2, produced commercially by UV tion, and UVB exposure (2,3,9). Concentration of irradiation of the fungal steroid ergosterol.
the precursor decreases with age, which is one rea- Unfortunately, fortification of milk with vitamin D son why older individuals may be vitamin D defi- has not been reliable. In one report on 94 samples, cient. Melanin is a natural sunscreen, competing 80% of the milk samples tested had either too much with provitamin D for UVB photons. As a result, vitamin D (by at least 20%) or were under fortified darker-skinned individuals may require fivefold or more increased sun exposure than fair-skinned indi-viduals to achieve the same serum 25OHD concen- Metabolism and Transport
tration (1). Sunscreens of SPF of 8 or higher of Vitamin D
substantially decrease vitamin D3 synthesis, as doesclothing and window glass (10). People who use Vitamin D is biologically inert. It is converted to veils, especially if dark-skinned, are at risk for vita- 25OHD in the liver and to its active form, 1,25(OH)2D in the kidney (3). Ingested vitamin D is Even spending time outdoors with exposed skin absorbed in the small intestine (50–80% is does not guarantee that sufficient vitamin D will be absorbed), enters the lymphatic system in chylomi- Clinical Reviews in Bone and Mineral Metabolism Vitamin D in the Prevention and Treatment of Osteoporosis CYP27A1. This mitochondrial enzyme carries out Sources of Vitamin D—Dietary and Sunlight 25-hydroxylation of vitamin D3 (but not D2), but itsmajor role is in bile acid synthesis. The most strik- ing phenotype of individuals lacking CYP27A1 activity is a severe cholesterol storage disease, cerebrotendinous xanthomatosis (21,22). Such per- sons also have some increased risk of low BMD and osteoporosis, indicating that CYP27AI has some importance in vitamin D metabolism.
CYP3A4 can carry out 25-hydroxylation of vitamin D2 (not D3), but is unimportant in this regard, as no mutations in this gene confer vitamin D or bone Blood concentration of 25OHD is not tightly con- trolled but is regulated by two main factors (1,3,17).
First is substrate availability, with increased 25(OH)D resulting from higher intake or cutaneous synthesis of vitamin D. Another important determi- nant is the CYP24A1 enzyme, which performs 24- hydroxylation of 25OHD. For 25OHD and for other vitamin D metabolites, 24-hydroxylation is the rate- limiting step on the degradative pathway. CYP24A1 is found in the liver and in all target tissues for 1,25(OH)2D (3). Activity of CYP24A1 is decreased by PTH (consistent with PTH’s role in promoting for- mation of active vitamin D). CYP24A1 activity is increased by 1,25(OH)2D, thus providing feedback 1,25(OH)2D is high. There are individuals who lack this feedback control (23,24). Persons with this con- dition—Williams’ disorder—have high concentra- tions of 25OHD and 1,25(OH)2D, as well as hypercalcemia, even though their CYP24A1 gene isnormal. They lack a 1,25(OH)2D-dependent tran-scription factor necessary for CYP24A1 to be made.
Williams’ disorder thus provides a clear example of crons, and is stored in fat, muscle, and skeletal tissue the importance of the degradative enzyme CYP24A1 (16). Vitamin D and 25OHD are transported in the bloodstream bound to a specific acid glycoprotein, Another factor that impacts 25OHD concentrations vitamin D binding protein (DBP) (3).
is binding to DBP, with 25OHD3 more tightly bound Vitamin D is converted in hepatic parenchymal than 25OHD2 (3). Very recent work demonstrated that cells to 25OHD. Three cytochrome P450 mixed- 25OHD3 is eliminated much more slowly than function oxidases can carry this out: CYP2R1, 25OHD2, and this difference may result from the more CYP27A1, and CYP3A4 (2,17–20). CYP2R1 is avid binding of 25OHD3 to DBP (25). For volunteers randomized to receive a single dose of 50,000 units of and generates most 25OHD. Persons with CYP2R1 either vitamin D2 or vitamin D3, area under the curve inactivating mutations have rickets but can be res- through day 28 was 60.2 ngd/L for vitamin D2 and 3 (p < 0.002). The authors con- Clinical Reviews in Bone and Mineral Metabolism cluded that D3 may be the preferable form of vitamin of calcium for mineralization of bone and for various metabolic functions, signal transduction, and nerve Following formation of 25OHD by the liver, the and muscle activity (1–3.) The active form of vita- active form of vitamin D, 1,25(OH)2D, is produced min D, 1,25(OH)2D, binds to the vitamin D receptor in the kidneys. Calcitriol, or 1,25(OH)2D3 refers (VDR). VDR is a member of the nuclear receptor specifically to the active form made from the natu- superfamily of ligand-activated transcription factors rally produced vitamin D3. Conversion of 25OHD to (also called the steroid receptor superfamily) (3).
1,25(OH)2D is carried out by the enzyme 25-hydrox- Tissues containing VDR include not only intestine, yvitamin D 1α-hydroxylase, or CYP27B1, found in bone, and kidney, but also less well-characterized mitochondria of renal tubular epithelial cells (2,17).
sites, such as pancreas, breast, testes, thymus, lym- Although this activity occurs in numerous tissues, phocytes, and macrophages (2). On the binding of the virtual absence of 1,25(OH)2D in the blood of 1,25(OH)2D to VDR, the complex binds to unoccu- anephric patients indicates that nonrenal tissues do pied retinoid X receptor and then to specific DNA not contribute importantly to circulating concentra- sequences (vitamin D response elements) (3,27).
Recruitment of transcription factors and increased Formation of 1,25(OH)2D by CYP27B1 activity transcription of specific genes follow. In the gut, syn- is tightly regulated (2). This can be appreciated by thesis of calbindin and other proteins increases considering that the enzyme product is present at epithelial calcium transport and enhances calcium only about 1/1000th the concentration of the sub- absorption. (See article entitled “Calcium Prevention strate [16–56 pg/mL for 1,25(OH)2D and 10–65 and Treatment of Osteoporosis” in this issue.) ng/mL for 25(OH)D] (2,3,26). Key regulators of Intestinal absorption of phosphorus is also CYP27B1 are PTH, serum phosphorus, phospha- enhanced by 1,25(OH)2D. In bone, 1,25(OH)2D has complex effects, promoting mineralization by main- PTH helps maintain serum calcium in conditions of taining a supersaturated calcium–phosphorus prod- vitamin D or calcium inadequacy (3,26). Parathyroid uct in the blood. In times of calcium deficit, cells have cell surface calcium sensing receptors that 1,25(OH)2D promotes osteoclastogenesis to enhance are exquisitely sensitive to decreased serum calcium.
calcium release from bone. Osteoblast differentia- PTH released in response to reduced serum calcium tion is also promoted by 1,25(OH)2D (28). (See arti- cle entitled Osteoporosis: Pathophysiology and New 1,25(OH)2D and thus enhancing intestinal absorption of calcium. Low serum phosphorus also directly stim- Several studies have examined the association ulates formation of 1,25(OH)2D. Phosphatonin, a between VDR gene polymorphisms and skeletal recently discovered regulator of phosphorus concen- health, with mixed results (29). Much of this work trations, also directly stimulates CYP27B1. Finally, examined polymorphisms recognized by the restric- 1,25(OH)2D itself provides negative feedback, tion enzymes BsmI, ApaI, and TaqI. VDR polymor- increasing the activity of CYP24A1. This enzyme car- phisms have been associated with fracture in some ries out 24-hydroxylation of 1,25(OH)2D, the first and studies but not others (3), and some polymorphisms rate-limiting step for its inactivation. Taken as a have been linked to variations in markers of bone whole, the initiating factors that ultimately lead to formation. VDR polymorphisms appear to be only increased synthesis of 1,25(OH)2D are calcium and/or modestly related to BMD, accounting for Z-score phosphorus deficits, whereas elevated concentrations differences of 0.15 to 0.2 (a difference of 0.15–0.2 of 1,25(OH)2D act as a brake on its own synthesis.
standard deviations between BMD of two persons ofthe same age and gender). In an interventional study Biological Functions and Mechanisms
in girls, an interesting interaction among calcium of Vitamin D Action
intake, BMD, and VDR polymorphism at the BsmIsite was found (30). Girls with lower BMD at base- The major physiological function of the vitamin line (BB phenotype) had higher increases in BMD in D system is to ensure adequate blood concentrations response to calcium supplements, but those with the Clinical Reviews in Bone and Mineral Metabolism Vitamin D in the Prevention and Treatment of Osteoporosis highest BMD at baseline (bb phenotype) remained Recommended Daily Vitamin D and Calcium Intake phisms could affect skeletal health is uncertain.
Message stabilization (production of longer lived VDR gene transcripts) or alternative splicing (form-ing two different VDRs with slightly different prop- erties) may play a role. There is also evidence that polymorphisms in the VDR promoter that alters the extent of intestinal VDR gene expression are associ- Recommended Intake of Vitamin D
Recommendations for vitamin D intake vary from 200 to 800 units/d (Table 2) (32–36). The Food and Nutrition Board revised its recommendations in 1997, and there is ongoing discussion as to what fur- ther changes are needed. There was insufficient data to formulate a recommended daily allowance (RDA), and the recommendations instead refer to adequate intake. For vitamin D, the question of ade- quate intake is complicated by the fact that many individuals acquire most of their vitamin D through sun exposure. For this reason, many studies on vita- min D adequacy focus on measurement of serum 25OHD rather than on vitamin D intake (37).
Concentrations of 25OHD can be expressed in two ways. To convert from nmol/L to ng/mL, multiply by 0.4. For example, 100 nmol/L = 40 ng/mL.
Epidemiology
Inadequate vitamin D status is increasingly recog- nized as a worldwide problem, seen in a variety of ethnic groups, countries, and seasons. Even in other- wise healthy, young individuals, vitamin D inade- quacy is a problem (38). One method to assess vitamin D adequacy is to determine whether a person a National Osteoporosis Foundation addition to National ingests the recommended quantity of vitamin D. Most Academy of Sciences recommendations (35); American persons do not. Average intake of vitamin D by young Association of Clinical Endocrinologists recommendation is women in the United States is 114 units daily, and for 800 units daily for elderly persons. (36).
older women the value is 92 units daily (32). In anationally representative sample of adults aged 65 andolder in the United Kingdom, average daily intake lyzed by ethnic group (41). Of 1426 white women, was 150 to 200 units (39). In a Danish study, 329 men 70% received no supplemental vitamin D, and 41% and women aged 35 to 65 consumed less than 200 had two or fewer servings of milk per week. Of 1546 units daily (40). In the National Health and African-American women, 80% received no supple- Examination Survey (NHANES) III, intake was ana- mental vitamin D, and 60% had two or fewer servings Clinical Reviews in Bone and Mineral Metabolism of milk per week. Inadequate vitamin D intake has results shed light on some recent concerns about also been documented in special populations, such as breast-fed infants of African-American women, as nursing homes. The mean vitamin D intake of nursing some infants have been diagnosed with rickets, home residents (n = 109) in one study was 379 units attributed to low vitamin D status in the mothers daily (42). In one nursing home study done by the (12). Another NHANES III analysis focused on vit- author, the mean intake of vitamin D from supple- amin D status in the winter for three ethnic groups ments among the 49 women studied (mean age 89) (47). For those aged 12 to 29, prevalence of vitamin D insufficiency (25OHD < 20 ng/mL) was 4% for Although assessing vitamin D intake has its uses, white women, 32% for African-American women, most studies now evaluate vitamin D status by mea- and 7% for Hispanic women. For those aged 30 to surement of 25OHD, which more closely relates to 59, prevalence of vitamin D insufficiency was 7% other measures of bone health, such as PTH and for white women, 31% for African-American BMD. Even so, prevalence estimates of vitamin D inadequacy are complicated by many factors. Theseinclude use of different thresholds to define insuffi- Clinical Effectiveness
ciency and deficiency, the assay used, and other vari-ables that influence concentrations, such as latitude The use of vitamin D in the prevention and treat- and season. Many studies now define the season and ment of osteoporosis has been evaluated as location when reporting prevalence estimates.
monotherapy in combination with calcium, and as The season of the year substantially impacts vita- adjunctive therapy with antiresorptive agents (e.g., min D status. Men and women living at 42° latitude bisphosphonates, selective estrogen receptor antago- in the United States exhibited means serum concen- nists, estrogen and hormone replacement therapy, trations of 22, 37, and 31 ng/mL for the periods of and calcitonin); and an anabolic agent (teriparatide).
February to May, June to September, and October to Vitamin D in combination with calcium has been January, respectively (44). In a study from southeast shown to decrease the incidence of vertebral and Australia including more than 3000 women, mean nonvetebral fractures and increase BMD (48).
serum 25OHD concentrations were 31 and 20 ng/mL Evidence for vitamin D as monotherapy for the pre- in summer and winter, respectively (14). Decreased vention or management of osteoporosis is less 25OHD in the winter was associated with elevated robust. Most clinical trials investigating the use of PTH, increased markers of bone resorption, and antiresorptive agents and teriparatide have used cal- increased proportion of falls leading to fracture. In a cium with or without vitamin D supplementation in study of 220 young healthy Finnish men ages 18 to the active and placebo groups; therefore calcium and 20, 25OHD was 17.6 ng/mL in July but only 9.6 in vitamin D supplements should be provided with these therapies to achieve desired outcomes.
Vitamin D adequacy has been studied in a variety of ethnic groups. Mean serum 25OHD concentration Fractures
of 18 Asian Indians living in South Carolina was 13 Many (49–54), but not all (55) clinical trials have ng/mL, compared with 30 ng/mL for 27 age- shown a favorable effect of vitamin D on vertebral matched white individuals living nearby (46).
and nonvertebral fractures. Most clinical trials inves- Recent work from NHANES III assessed vitamin D tigating the benefit of vitamin D used concomitant status in African-American women in comparison to calcium therapy or ensured that dietary calcium white women. Of 1546 African-American women of reproductive age (ages 15–49), the percentage of In one meta-analysis, data was pooled from stud- women with serum 25OHD concentration below 15 ies using vitamin D and from studies using its ng/mL was 42.4%, but this was only 4.2% among hydroxylated analogs calcitriol [1,25 (OH)2D3] or 1426 white women aged 15 to 49 (41). Twelve per- alphacalcidol (1α-hydroxyvitamin D3) (56). These cent of African-American women and 0.5% of white studies included those where these agents were used women had concentrations below 10 ng/mL. These alone or in combination with calcium. The pooled Clinical Reviews in Bone and Mineral Metabolism Vitamin D in the Prevention and Treatment of Osteoporosis data from eight clinical trials (n = 1130) studying the The studies included those where vitamin D or cal- effect of vitamin D or its hydroxylated analogs on citriol were used alone or in combination with cal- vertebral fractures show a relative risk of 0.63 (95% cium. The effect of vitamin D was significant for CI, 0.45–0.88, RR p < 0.01). Based on pooling results from six clinical trials (n = 6187), the relative 0.17–1.54; p = 0.01) and the femoral neck at the end risk for nonvertebral fracture was 0.77 (95% CI, of study (WMD = 0.98; 95% CI 0.10–1.85; p = 0.57, 1.04, RR p = 0.09). In these studies, the ratio of 0.03). The effect of calcitriol was significant for all subjects randomized to standard vitamin D com- sites at doses above 0.43 µg daily, with WMD rang- pared to calcitriol was approx 7:1. (See section enti- ing from 2.45 for spine to 9.79 for forearm.
tled“Other Vitamin D Analogs” for further analysis A 2-yr study investigated the effect of 400 units of vitamin D3 on bone turnover and bone loss from hip In a study of 3270 elderly French women, those and distal radius in women living in apartments or who received 1200 mg elemental calcium and 800 homes for the elderly. An increase in BMD was units of vitamin D3 daily for 18 mo had 32% fewer greatest at the femoral neck in the first year but these nonvertebral fractures and 43% fewer hip fractures results were not statistically significant (57). In one that those receiving placebo (52). These results were prevention trial, a combination of 700 units of vita- sustained at 36 mo (53). In a 3-yr prevention trial of min D3 and 500 mg of elemental calcium given daily 389 men and women older than 65 yr, 700 units of to 389 American men and women 65 yr and over vitamin D3 and 500 mg of elemental calcium given resulted in an increase of BMD at the femoral neck daily resulted in a relative risk for nonvertebral frac- vs placebo (0.50% ± 4.80% and –0.70% ± 5.03%; tures of 0.5 (95% CI 0.2–0.9; p = 0.02) vs placebo p = 0.02); at the spine (2.12% ± 4.06% and 1.22% ± (51). Overall, the evidence is good for fracture pre- 4.25%; p = 0.04); and total body (0.06% ± 1.83% vention by a combination of calcium and vitamin D.
and –1.09% ± 1.71%; p < 0.001) (51). Although the One study investigated the use of vitamin D3 alone studies quoted above indicate that vitamin D or cal- compared to placebo for up to 3.5 yr in 2578 men and citriol can improve BMD, there is no compelling evi- women age 70 yr and older (55). No difference in dence that these agents alone (without calcium) fracture incidence was seen. However, in that study only 400 units daily of vitamin D3 were given. A veryrecent study using a higher dose indicated that vita- Vitamin D Plus Other Pharmacological Agents
min D3 alone may be efficacious (49). A total of 2686 Key trials with bisphosphonates, selective estro- men and women aged 65to 85 yr were randomized to gen receptor modifiers, estrogen and hormone 100,000 units of vitamin D3 or placebo given every 3 replacement therapy, calcitonin, and teriparatide for mo for 5 yr. Those given vitamin D3 had a signifi- the treatment of osteoporosis did not use true cantly decreased risk of overall fractures (relative risk placebo control because the placebo groups used 0.78) and of hip, forearm, or vertebral fracture com- supplemental calcium with or without vitamin D bined (relative risk 0.67). To summarize, although the supplementation (58–64). Although these clinical evidence for fracture prevention by vitamin D alone trials do not attest to any specific skeletal benefit is mixed, this most recent study suggests that vitamin from vitamin D, it is important that patients be D supplementation alone can prevent fractures.
treated likewise, so that maximal benefit from antire-sorptive or teriparatide therapy can be realized. In Bone Mineral Density
current clinical practice, antiresorptive therapy is One meta-analysis reported the weighted mean sometimes prescribed without assessing or correct- difference (WMD) of bone density for total body, ing the patient’s calcium or vitamin D deficits.
lumbar spine, combined forearm, and femoral neck For men, osteoporosis studies including vitamin after treatment with vitamin D or calcitriol (56).
D were in combination with other agents, including (WMD is the difference in BMD between treatment alendronate and teriparatide (65,66). Calcitriol alone and control groups, using the percentage change has not been proven to be effective in treating male from baseline in the treatment and placebo groups.) Clinical Reviews in Bone and Mineral Metabolism Evidence for Skeletal Benefits for Vitamin D
Finally, another vitamin D analog, 1α,25-dihy- Analogs and Experimental Agents
droxy-2β-(3-hydroxypropoxy) vitamin D3 (ED-71) Although approved for other uses, calcitriol has is undergoing clinical studies. A phase II trial with also been studied for osteoporosis treatment. Many 109 osteoporotic patients has shown that oral daily of the early studies on BMD have been conflicting, administration of ED-71 (0.25–1.0 µg daily) for 6 with several showing increased BMD, whereas oth- mo increased spine BMD and suppressed markers of ers showed no benefit. However, a recent meta- analysis has indicated that calcitriol may be effective Other Potential Benefits of Vitamin D
(68). (This was an analysis of both calcitriol and Although best known for its role in calcium alphacalcidol treatment trials.) Inclusion criteria absorption and bone health, other roles for vitamin D were that the studies had to be randomized con- are being explored. Although exciting, much of this trolled studies of BMD or fracture in subjects, literature is epidemiological and requires confirma- whether or not exposed to corticosteroids. Seventeenstudies (nine on calcitriol) met these criteria and were included. Efficacy of calcitriol in preventing A role for vitamin D in muscle function is sug- lumbar spine bone loss was demonstrated, with a gested by the presence of calcitriol receptors in positive effect size (ES) of 0.41 (p < 0.001). (ES is a skeletal muscle and the effect of calcitriol on intra- method to compute standardized mean differences cellular calcium regulation in muscle (73). With between treatment vs control groups.) Calcitriol aging, there is also reduced VDR expression in compared to placebo significantly reduced the risk human muscle (74). Vitamin D insufficiency is asso- for overall fracture (relative risk 0.52 [0.41, 0.66]) ciated with muscle weakness, limb pain, and and vertebral fracture (relative risk 0.52 [0.41, decreased physical function, and these symptoms 0.67]). Although this was a positive analysis, it may respond to vitamin D replenishment (75–77). Risk of not be definitive. One other recent meta-analysis falling is associated with the combination of low vit- concluded that calcitriol was not efficacious in pre- amin D status with elevated PTH, and fall risk is venting fractures (69). This analysis used different reduced with vitamin D repletion (78–80).
criteria for inclusion of studies and did not include A possible association between vitamin D status one of the largest (but heavily criticized) calcitriol and heart failure has also been examined, spurred by studies (70). There will likely continue to be debate the knowledge that cardiac myocytes possess VDR about the efficacy of calcitriol, and it is not FDA- and calcitriol-dependent calcium channels and that approved for osteoporosis treatment or prevention.
vitamin D normalizes contractility in experimental Another vitamin D analog, 1α-hydroxyvitamin vitamin D deficiency. Heart failure patients (New York Heart Association grade 3 and 4) compared to 3 (alphacalcidol) has been examined, but most studies were small and flawed (71). This compound age matched controls had increased serum concen- has been examined in a recent meta-analysis, where trations of NT-proANP (a marker of disease sever- eight of the studies were on alphacalcidol (68).
ity), reduced circulating concentrations of 25OHD, Efficacy of alphalcidol in preventing lumbar spine and a tendency to higher PTH concentrations (81).
bone loss was reported, with a positive ES of 0.48 Recent work supports a protective effect of vitamin (p < 0.001). Alphacalcidol compared with placebo D intake with regard to multiple sclerosis. In the significantly reduced the risk for overall fracture Nurses Health Study, the age-adjusted relative risk for (relative risk 0.52 [0.45, 0.59]) and vertebral fracture development of multiple sclerosis was significantly (relative risk of 0.53 [0.46, 0.61]). Again, as in the reduced for those in the highest quintile of total vita- case of calcitriol discussed above, this analysis may min D intake at baseline compared to those in the low- not be definitive, and another recent meta-analysis, est quintile (82). Vitamin D and its analogs have with different inclusion criteria, concluded that antiproliferative effects. This property has been alphacalcidol was not efficacious in preventing frac- exploited in the use of a vitamin D analog (cal- tures (69). This agent is approved in Japan for osteo- cipotriene) to treat psoriasis. Even more exciting, a porosis treatment, but is not FDA-approved.
number of studies have indicated that vitamin D Clinical Reviews in Bone and Mineral Metabolism Vitamin D in the Prevention and Treatment of Osteoporosis Calcium–Vitamin D combinationsCaltrate 600 + D a Units unless otherwise noted.
b Prescription product.
c Generic available.
intake/exposure or higher concentrations of 25(OH)D of vitamin D3, is also available. Many multivitamins may be associated with a lower risk of breast, colon, are formulated with 400 units of vitamin D.
and several other cancers (27,83). Finally, a possiblerole for vitamin D in rheumatoid arthritis has been Kinetics
studied. The Iowa Women’s Health Study showed that Vitamin D is fat-soluble and is readily absorbed vitamin D intake was inversely associated with the from the small intestine. It is stored primarily in the risk of developing rheumatoid arthritis (84).
liver but also resides in fat, muscle, and skin.
Elimination half-lives (t1⁄ ) are as follows: 25(OH)D Vitamin D Products
5–8 h. Very recent work has indicated that 25OHD3 Table 3 provides information on a number of has a substantially longer elimination half-life than commercially available vitamin D products. These 25OHD2 (25). Excretion of vitamin D metabolites products include vitamin D2 (ergocalciferol) and vit- occurs primarily in the bile, and a small percentage amin D3 (cholecalciferol). Calcitriol, the active form Clinical Reviews in Bone and Mineral Metabolism Individuals Who May Benefit From Measurement of Vitamin D Status and Who May Warrant Supplementation With Prescription Vitamin D (34,85–92) Decreased cutaneous synthesis; reduced absorption; decreased Darker-skinned or veiled individuals, particularly if living in higher Inflammatory bowel disease or malabsorption Decreased absorption of fat soluble vitamins Renal osteodystrophy (may require calcitriol) Vitamin D deficiency leading to secondary hyperparathyroidism and bone loss; severe vitamin D deficiency leading to hypophosphatemia, hypocalcemia, and osteomalacia These agents were tested, and work best, with calcium and Increased risk of bone loss, tendency toward negative calcium Enzyme-inducing antiepileptic drug therapy Drug–Drug Interactions
D (Table 4). Persons of advanced age are susceptibleto low vitamin D status for a variety of reasons. These Few drug interactions exist with vitamin D.
include poor sunlight exposure, decreased previtamin Enzyme-inducing antiepileptic drugs increase D3 concentrations in the skin, decreased production metabolism of 25OHD, so that increased supple- of vitamin D3 in response to sunlight, decreased mentation with vitamin D may be needed to prevent intestinal absorption of vitamin D, decreased vitamin D deficiency and the potential for osteoma- parathyroid gland responsiveness, and decreased lacia or osteoporosis (85). This is more problematic renal capacity to form 1,25(OH)2D (1,86–88).
with persons taking multiple antiepileptic drugs or Disease interactions for vitamin D are related to with institutionalized patients, rather than otherwise malabsorption or altered metabolism, most of which healthy individuals on monotherapy (2). Although result in decreased vitamin D status. If uncorrected, not commonly listed as a drug interaction, there is a such individuals are at risk for osteoporosis or osteo- very important interplay between calcium and vita- malacia (89,90). Individuals with inflammatory min D. With vitamin D insufficiency, intestinal cal- bowel disease (e.g., Crohn’s disease or celiac sprue) cium absorption is impaired, so that even with or others with fat malabsorption (e.g., postgastrec- substantial calcium intake (2 g/d), most individuals tomy) may absorb lipid soluble vitamins poorly will undergo negative calcium balance (7). There are (91,92). People with very low vitamin D status from no food interactions with vitamin D.
malabsorption or other causes may require greatlyincreased supplementation with vitamin D, even, on Drug–Disease Interactions and Other
occasion, up to 50,000 units twice a week, with Influences on Vitamin D Status
appropriate monitoring (author’s own experience).
Although vitamin D undergoes hepatic conver- Important influences on vitamin D status in the sion to 25OHD, this step is rarely compromised in population as a whole are those related to endoge- patients with hepatic dysfunction. However, nous synthesis, ingestion, and absorption of vitamin 1,25(OH)2D synthesis is decreased in renal insuffi- Clinical Reviews in Bone and Mineral Metabolism Vitamin D in the Prevention and Treatment of Osteoporosis ciency, and some patients will require calcitriol to approx 32 ng/mL). This point is particularly impor- promote calcium absorption and avoid secondary tant as the average intake of calcium in the United States is far below the recommended intake, so that Rarely, patients with lymphoma or granulomatous robust vitamin D status is helpful. Finally, in consid- disease (e.g., active sarcoid or tuberculosis) will ering “healthy and reasonable” vitamin D status, it is exhibit ectopic and inappropriate formation of cal- estimated that sun exposure of evolving humans in citriol, with associated risk of hypercalcemia (94).
East Africa would have provided a 25(OH)D con- Supplementation of such patients with pharmacolog- ical doses of vitamin D should be carried out cau- For individuals without sufficient sun exposure, it tiously and with medical supervision.
is important to determine how much supplementalvitamin D is necessary to achieve specific concentra-tions of 25OHD. Although this question had been Clinical Usage
studied previously, results had not been clear-cut, Appropriate use of vitamin D involves considera- owing to limited time frame or to poor control of sun exposure or vitamin D intake. To obtain definitiveanswers, researchers gave graded doses of vitamin D over 20 wk to individuals with little sun exposure 2. How much vitamin D is necessary to achieve this and limited dietary input of vitamin D (97). It was found that a given amount of vitamin D input (400 units/d) translated into a given increment of 25OHD 4. How can patients acquire the vitamin D they (an increase of 2.8 ng/mL). For example, to increase a person’s vitamin D concentration from 20 to 34 5. How should vitamin D status be monitored, if at ng/mL, that person’s vitamin D intake would need to be increased by 2000 units/d. Thus, it is understand- 6. How should patients with chronic renal insuffi- able that individuals who are housebound, even if ciency who cannot synthesize enough calcitriol they drink some milk (200 units in 2 cups), and take a multivitamin (400 units) can still be vitamin D Answers to the question regarding vitamin D ade- quacy are developing. The best overall measure of Guidelines regarding vitamin D intake are pro- vitamin D status is serum 25OHD. (2,3,32) vided in Table 2, and although there is debate over Previously, the lower limit of acceptable serum these recommendations (see studies mentioned ear- 25(OH)D (10 ng/mL, still used as the lower refer- lier) guidelines provide a starting point for clinicians ence range by many laboratories) is the concentra- and patients. Using these guidelines and information tion necessary to avoid osteomalacia and rickets.
about vitamin D content of food and supplements Recent work has better defined the meaning of vita- (Table 1), individuals can assess their intake and min D adequacy. In order to avoid secondary hyper- decide how to improve it if necessary. For those parathyroidism, with accelerated bone turnover, without regular sun exposure, supplementation bone loss, and risk of fracture, 25OHD needs to be at would be advisable. To achieve an 800 units/d higher least 15 to 25 ng/mL (95). Clinical studies provided intake, a reasonable choice would be to take one even better estimates: Subjects’ blood concentrations multivitamin (400 units), two tablets of calcium/vit- were maintained at 20 ng/mL 25OHD and their abil- amin D (500 mg/100 units each), and two more ity to absorb calcium was compared with that of sub- glasses of milk (200 units). Another option is to take jects maintained at 34 ng/mL (8). Subjects at 34 a pure vitamin D supplement (400–1000 units), ng/mL absorbed 65% more calcium. Other work available in some pharmacies. Although vitamin D is showed that people at 48 ng/mL did not absorb cal- safe, clinicians should bear in mind the current rec- cium much better than those at 30 ng/mL (96). This ommendation of up to 800 units/d for routine sup- work suggests that there is a concentration at or plementation; alternatively, the use of 1000 units/d is above which calcium absorption is optimum, of often used and considered safe by bone experts (98).
Clinical Reviews in Bone and Mineral Metabolism Little information is available to guide the physi- Adverse Reactions
cian, pharmacist, or the patient regarding monitoringof vitamin D. It is impractical, expensive, and unnec- Vitamin D has a very wide margin of safety, and essary to measure most people’s vitamin D status.
adverse reactions to it are attributable to hypercal- New public health measures encouraging further vit- cemia. Signs and symptoms of hypercalcemia amin D supplementation of foodstuffs, and reason- include weakness, nausea, anorexia, renal impair- able and safe sun exposures, may be helpful to the ment, cardiac arrhythmia, calcification of soft tis- population as a whole and may be more beneficial sues, and bone demineralization (3). Symptomatic than measuring 25OHD. Measurement in high-risk cases of hypercalcemia associated with vitamin D individuals, however, is reasonable (Table 4), and intoxication have not been reported for exposures of vitamin D supplementation for those with 25OHD less than 10,000 units/d for an extended period of below 32 ng/mL is reasonable (98). In the author’s time, except for rare conditions associated with clinic and that of several colleagues, a common rou- hypersensitivity (101). Although massive overdoses tine is to replete the person with 50,000 units of vit- of vitamin D have been associated with severe amin D orally three times a week for 6 or 8 wk, hypercalcemia and can be fatal, such cases are very followed by a long-term regimen of 50,000 units of rare. The tolerable upper intake level for adults is vitamin D once or twice a month, depending on 2000 units daily (32). For patients who need more, response (99). For those individuals with very low monitoring of vitamin D status is recommended.
25OHD concentrations at baseline, particularly inthe elderly, measurement of intact PTH also may be Drugs of Choice and Patient
warranted. Those found to have low 25OHD, high Selection Issues
PTH, and low or normal calcium most often havesecondary hyperparathyroidism. As the patient is Drugs of choice for achieving vitamin D adequacy given vitamin D, and as the hypovitaminosis D is are presented in Table 3. For healthy young adults, resolved, PTH will ordinarily decrease (100).
health care providers should encourage outside activ- For patients with chronic renal insufficiency, par- ity with some sun exposure (10–15 min/d exposure in ticularly end-stage renal failure, management of the spring, summer, and fall, with exposed arms and calcium–vitamin D–phosphorus–PTH axis is com- face) and some consumption of fortified foods. One plex but is important for prevention and treatment of multivitamin daily, plus calcium with vitamin D, is renal osteodystrophy and osteoporosis. Depending on reasonable for many persons, especially if older or the degree of renal failure, the patient may require with low intake. Be aware that vitamin D2 and vita- calcitriol. Such patients, even if given vitamin D and min D3 may not be therapeutically equivalent, as achieving 25OHD above 32 ng/mL, will still exhibit recent work has suggested that vitamin D3 may be inappropriately high PTH concentrations and ele- more potent than vitamin D2 (25). Advise patients to vated alkaline phosphatase, because their kidneys are avoid cod liver oil (500 units of vitamin D and 500 units of vitamin A per 5 mL), or to use very modestly.
administered at 0.25 to 1 µg daily in such patients.
Vitamin A intake above the RDA (2330 units for Serum calcium must be closely monitored, as cal- women, 3000 for men) is associated with bone loss, citriol has significant hypercalcemic potential.
and dietary intake is approx 2000 units/d (102).
Monitoring of calcitriol concentrations is not usefulnor clinically indicated (93). Serum calcium should Proper Medication Use and Patient
be “corrected” with albumin (“corrected calcium” = Counseling
measured calcium + (0.8 × [4-measured albumin]).
New guidelines from the National Kidney Patients should be encouraged to make appropri- Foundation provide guidance on management of such ate lifestyle changes to protect their long-term skele- patients, including goals and time frame for monitor- tal health, in addition to achieving adequate vitamin ing of serum creatinine, phosphorus, calcium, alka- D. Smoking cessation, moderation of alcohol use, line phosphatase, and PTH (93).
weight-bearing activity, and fall prevention when Clinical Reviews in Bone and Mineral Metabolism Vitamin D in the Prevention and Treatment of Osteoporosis necessary should be advised. For the patient taking until the serum 25(OH)D concentration is adequate.
more than one calcium/vitamin D supplement, Remember that vitamin D kinetics are very slow.
divided doses are recommended, to improve absorp- Wait several weeks, or even 3 to 4 mo before remea- tion of calcium and also to provide better protection suring 25(OH)D after starting on vitamin D therapy.
against secondary hyperparathyroidism (103).
Advise patients about obtaining a healthy “dose” Explain to patients that vitamin D does not have to of sun. Ten to 15 min during the day a few times a be taken at the same time as calcium. Finally, make week, with the hands, face, and arms exposed is sure the patient understands that vitamin D is impor- often sufficient. Let patients know that sunscreen tant to help calcium work and to keep bones healthy.
and window glass, block vitamin D synthesis.
Advise patients to use combination calcium/vitamin Preventing/Resolving
D rather than calcium alone. This is not going to be Medication-Related Problems
harmful and may allow the patient to get just enoughD in their system, at no or little added cost.
For persons who have difficulty swallowing, liq- uid formulations of calcium and of vitamin D are References
available. For patients taking prescription strengthvitamin D, encourage them to use their calendar.
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Gabriele_maggio.odt

POLITICAMENTE ANNO VIII, N. 81 – MAGGIO 2013 Si allarga il fronte anti-euro I termini fissati dall’Unione Europea e dal Fondo Monetario Internazionale per il “salvataggio” di Cipro ( rectius , delle banche cipriote e tedesche) rischiano di provocare un panico finanziario di proporzioni globali. La versione corrente del piano – che richiederà un voto del Parlamento di Nicosia

Curriculum vitae:

Curriculum Vitae: DARRYL I. MACKENZIE B.Sc. (Statistics), University of Otago, New Zealand, 1995D.Ap.Stat., University of Otago, New Zealand, 1998Ph.D. (Statistics), University of Otago, New Zealand, 2002PROFESSIONAL BACKGROUNDSince 1997 I have been applying statistical techniques to address questions of interest for a wide range of animal species including seabirds, grizzly bears, sea lio

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