Clinical Comparison of Vitamin D Metabolites

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VITAMIN D CLINICAL COMPARISON UpDates OF VITAMIN D METABOLITES Andrea Giusti, Giuseppe Girasole, Dario Camellino, Gerolamo Bianchi Rheumatology Clinic, Department of Locomotor System, “La Colletta” Health Board 3, Genoa

INTRODUTION imately 80%) of the vitamin D requirements Abstract In the last 20-30 years, increasing awareness (vitamin D3), while lower quantities (approx- The effects of cholecalciferol and of several of the role of vitamin D in the pathogenesis imately 20%) of vitamin D3 and vitamin D2 vitamin D metabolites have been investigat- of some musculoskeletal and extra-skeletal dis- should come from dietary sources [1]. ed and are now available for clinical use. Vitamin D3 skin production is greatly influ- The numerous and important differences eases, together with substantial epidemiologic between vitamin D metabolites, both in evidence on the prevalence of hypovitamino- enced by seasonal change (lower during win- pharmacokinetics and for clinical purposes, sis D in the general adult population and in ter), latitude, the surface area and thickness need to be taken into account when deter- the elderly, have given rise to an ever-growing of the skin exposed to sunlight (and perhaps mining the most appropriate drug for the debate concerning the appropriateness of the also the use of sunscreens), and age (lower in treatment and/or prevention of vitamin D the elderly) [1]. A lower dosage of vitamin D3 deficiency. strategies for the prevention and treatment of In this context, and based on data from clini- vitamin D deficiency [1-9]. can be obtained from food, in particular from cal studies, cholecalciferol appears to be the A number of scientific works have investigated animal fats, while the amount of vitamin D3 in preferred supplement in the prevention and the use of cholecalciferol and vitamin D me- vegetable fats is totally negligible [1]. Dietary treatment of vitamin D deficiency. In conjunc- tion with other therapies, it is also used in tabolites (calcifediol in particular) for the pre- intake of vitamin D is significantly higher in those countries where vitamin D fortified foods the prevention of primary and secondary vention and treatment of vitamin D deficiency fractures associated with bone fragility in pa- [1-9]. Undoubtedly, the great number of these with cholecalciferol are allowed [1]. tients with osteoporosis receiving antiresorp- randomized, controlled trials (RCTs) have pro- Vitamin D is highly liposoluble, such that upon tives or osteoanabolic medication. duced a significant advance in our knowledge absorption it is stored in fatty tissues and re- Based on current evidence, the use of other metabolites must be limited to specific medi- on this topic, highlighting extremely important leased in small quantities. This explain why obese subjects are at higher risk of vitamin D cal conditions, such as chronic renal insuffi- clinical aspects [1, 3, 5, 6]. However, the ciency or hypoparathyroidism (alfacalcidol deficiency, as it becomes “diluted” in the high- quantity, quality (not always high) and heter- and calcitriol), malabsorption syndrome, er body mass [1]. As vitamin D does not stay ogeneity of these published studies have also severe obesity or hepatic insufficiency (cal- in the body for very long, its concentration in generated some doubts on the issue. cifediol). the bloodstream is very low (1-2 ng/mL) [1]. The aim of our narrative review is to describe In the liver, vitamin D is converted into 25-hy- the main attributes of vitamin D metabolites droxyvitamin D [25(OH)D] by the enzyme and to define their role in daily clinical prac- 25-hydroxylase. This transformation process tice, with the aim of aiding physicians in can also take place in the presence of a signif- choosing adequate strategies to use in pa- icant reduction in the hepatic tissue function, tients with proven vitamin D deficiency or with although a high prevalence of hypovitamin- a risk of hypovitaminosis D. osis D is evident in patients with correlated chronic hepatitis HCV [1]. VITAMIN D PRODUCTION AND Calcifediol, or 25(OH)D, has a high affinity METABOLISM for the vitamin D binding protein (VDBP) and In general, the term vitamin D refers represents the main vitamin D blood metab- to both vitamin D3 (cholecalciferol), produced olite. Its concentrations are the most reliable by animals and humans, and vitamin D2 representation of the vitamin D status of indi- (ergocalciferol), produced by plants [1]. En- viduals [1]. Serum 25(OH)D concentrations dogenous synthesis is the principal source of constitute an accurate indicator of our storage vitamin D for the organism; it derives from the of vitamin D. As a result, the question of vita- conversion of 7-dehydrocholesterol after skin min status (deficiency, insufficiency and suffi- Correspondence exposure to UV rays of a specific wavelength. ciency) is exclusively based on serum 25(OH) ANDREA GIUSTI This mechanism should produce most (approx- D levels (Table I). [email protected]

VITAMIN D - UpDates 26 2018;1(2):26-31; https://doi.org/10.30455/2611-2876-2018-03e In part, 25(OH)D is a hydrophilic metabo- an active metabolite) produces a biologi- Cholecalciferol is normally stored in the adi- lite; it is stored only in the liver and muscles cal response at the cellular level [1]. Such pose tissue, from where it is slowly released [1]. Its half-life is shorter than that of vitamin a response is produced both by triggering [1]. For this reason, its blood half-life is very D, such that it is able to satisfy the organism’s gene transcription (genomic mechanism) short (estimated T1/2 = 19-25 hours), while requirements for no more than 12-18 days and through the action of cellular second its functional half-life (several weeks) is defi- [1, 4]. 25(OH)D has a low affinity for the messengers or the phosphorylation of some nitely longer (in correlation with its slow re- specific vitamin D receptor and thus needs to proteins (non-genomic mechanism) [1]. Vita- lease from the adipose tissue) [4], making be transformed into calcitriol, or 1,25-dihy- min D receptors are ubiquitous in the body. it an extremely flexible and adaptable sub- droxyvitamin D [1,25(OH)2D], to become stance to use in daily clinical practice and metabolically active [1, 4]. CHOLECALCIFEROL, ERGOCALCIFEROL rendering possible intermittent administration The conversion of 25(OH)D into AND VITAMIN D METABOLITES regimes [1, 2]. 1,25(OH)2D by the action of the 1-al- In addition to the two natural forms of vi- Cholecalciferol is available on the market pha-hydroxylase enzyme takes place pre- tamin D – vitamin D3 (cholecalciferol) and for oral and intramuscular use. With the ex- dominantly in the kidneys, but it can also vitamin D2 (ergocalciferol) – many other ception of specific clinical conditions (ma- occur in other tissues [1]. Most of the pro- supplements/metabolites with the same vita- labsorption syndrome), oral administration duction of 1,25(OH)2D, whose most impor- min D activity are available for daily clinical is preferable to intramuscular injection be- tant role is to control mineral metabolism, practice [1, 4]. Some of them, such as cal- cause it is more effective in boosting serum occurs in the renal proximal tubules. The cifediol, were already clinically synthetized 25OHD [11, 12]. production of 1,25(OH)2D by the action of and utilized in the last century. Other forms, Clinical studies have employed many ad- the 1-alpha-hydroxylase enzyme involves the meanwhile, have been synthetized and pri- ministration regimes and different doses of presence of the parathyroid hormone (PTH) marily employed in nephrology (for exam- cholecalciferol, ranging from 400 to 4000 and is in part modulated by serum calcium ple, paricalcitol) [4]. IU/day and 25,000 to 50,000 IU per and phosphorus levels [1]. 1,25(OH)2D is A comprehensive discussion of all vitamin month [4, 6, 13-18]. Figure 1 illustrates the not stored at tissue level and has a very short D metabolites, particularly those which are effect – in terms of mean increase of serum half-life [1, 4]. mainly used in nephrology, is not the intent 25OHD (ng/mL) after three months – of Renal insufficiency progressively reduces of our review. Our presentation will therefore different doses and therapeutic treatments 1,25(OH)2D production [1]. Nevertheless, focus on the most common types of vitamin with cholecalciferol. The lowest doses (e.g., a significant decline in 1-alpha-hydroxylase D utilized in daily clinical practice; it will aim 400-600 IU/day) have proved to be inef- enzyme activity, such that normal hormone to describe their properties (Table 2) and to fective in achieving clinical endpoints (e.g., levels are compromised, is only detected briefly summarize clinical data obtained reduction of risk for fractures) [15]. Some when associated to severe renal function im- from RCTs. RCTs have also investigated the effectiveness pairment (generally 4-5/5D stage) [1, 10]. of massive doses (boli) of cholecalciferol, However, it should be emphasized that even Cholecalciferol with mixed results for clinical outcomes such when renal 1-alpha-hydroxylase enzyme ac- Cholecalciferol (vitamin D3) is the natural form as falls and fractures [1, 2, 6]. It is there- tivity is severely compromised, 25OHD lev- of vitamin D of animal and human production. fore recommended not to exceed the bolus els must be kept within the normal range to Cholecalciferol (vitamin D3) is a prohormone, dosage of 100,000 IU and to distribute the ensure an adequate substrate for extra-renal the precursor of the two vitamin D hydroxy- administration of any higher therapeutic dos- 1-alpha-hydroxylase [1, 10]. lated forms [25OHD and 1,25(OH)2D]; it age (aiming to attain the optimal serum val- By binding with a specific receptor (VDR, therefore needs to undergo two processes of ue of less than 30 ng/mL) over the course of which is present both in the nucleus and hydroxylation before being transformed into its two weeks [1, 2]. Recently, the Italian soci- in the cell membrane), 1,25(OH)2D (as metabolically active form [1, 4]. ety SIOMMMS proposed a strategy for the prevention and treatment of vitamin D deficiency with cholecalciferol (Table 3), based on basal vitamin D status (25OHD) [2]. The TABLE I. cholecalciferol doses shown in Table 3 must Interpretation of blood levels of 25(OH)D (Adami et al. 2011, mod.; Rossini et al. 2016, be considered standard, although they are mod.) [1, 2] susceptible to variations in relation, for ex- 25OHD Units ample, to the existence of risk factors (such DEFINITION nmol/l ng/ml as obesity) that could reduce the effect of cholecalciferol in increasing serum 25OHD Severe deficiency < 25 < 10 values [16]. Deficiency 25-50 10-20 In the context of vitamin D metabolites cor- Insufficiency 50-75 20-30 related to vitamin D deficiency, cholecalciferol has by far been the one to attract most Optimal Range 75-125 30-50 attention, both in clinical studies for the pre- Excess > 250 > 100 vention and treatment of hypovitaminosis D and in RCTs evaluating its effectiveness on Intoxication > 375 > 150 skeletal (falls and fractures) and extraskeletal

27 (e.g., pneumonia and neoplasia) endpoints sired range (30-50 ng/mL) [1, 2, 13, 14, RCTs and their meta-analyses have shown [1-3, 6]. A systematic discussion of RCTs on 16-18]. The definition of an appropriate that cholecalciferol, when administered in cholecalciferol falls outside the aims of our dose must take into account both the basal appropriate doses and therapeutic regimes review, which is limited to describing the serum 25OHD value and other clinical fac- and when associated with adequate calci- most important findings in the field of osteo tors that may influence treatment response um supplementation – either through foods metabolic disorders. (e.g., body mass index, age, pathologies (only dietary calcium) or supplements – is Numerous RCTs have evaluated the efficacy and pharmacological therapies) [1, 2, 16]. able to produce a significant reduction in of cholecalciferol in normalizing and main- The prevention and treatment strategies de- the risk of femur and non-vertebral fractures taining the optimal level of serum 25OHD scribed in Table III summarize a part of the in at-risk populations (such as the elderly and (> 30 ng/mL) [1, 2, 11-18]. These studies evidence from these RCTs [2]. adults with low 25OHD levels) [1, 2, 5, 6]. have shown that when used at appropriate Cholecalciferol has noticeably been the fo- Reduced fracture risk was in part attributed doses and in suitable therapeutic regimes cus of the greatest number of RCTs that aim to a significant reduction in the risk of falls. cholecalciferol was able to efficiently nor- to evaluate the efficiency of this metabolite Even if the findings of these RCTs are not com- malize 25OHD and keep it within the de- in reducing the risk of fracture [6]. These pletely consistent, reports of higher scientific

TABLE II. Half-life and commonly used doses of vitamin D and its metabolites in clinical practice (Mazzaferro, et al. 2014, mod.) [4]. CHOLECALCIFEROL ERGOCALCIFEROL CALCIFEDIOL ALFACALCIDOL CALCITRIOL Blood: 19-25 hours Blood: 48 hours Half-life 10-22 days 12 hours 5-8 hours Functional: many weeks Functional: 2 months or less 400-4,000 IU/day Dose Range 800-2,000 IU/day (most commonly evaluated in 5,000-10,000 IU/week 5-20 μg/day 0.5-5 μg/day 0.25-1 μg/day 50,000 IU/week clinical studies) 25,000-50,000 IU/month

quality allow us to estimate a risk reduction in subjects treated with cholecalciferol of 16-30% for femur fracture and of ca. 14% for non-vertebral fracture [5, 6]. It should be emphasized that these findings derive from trials in which cholecalciferol was administered to appropriate patients (with, that is, vitamin D deficiency), and above all in suitable doses (between 800 IU and 2,000 IU/ day) [5, 6, 15]. In the clinical studies, the administration of boli less than 100,000 IU turned out to be safe and free of side effects, including hypercalcemia and hypercalciuria [1, 2, 4, 6]. Finally, to provide a comprehensible frame- work for the use of cholecalciferol in clinical practice, we should highlight several points Mean serum 25(OH)D increment (ng/mL) of undeniable importance: • cholecalciferol has proven to be effective in reducing the risk of femur and 1000 2000 5000 100,000 300,000 600,000 non-vertebral fracture when it is used in U/day IU/day IU/day IU/bolus IU/bolus IU/bolus doses that allow an appropriate level of 25OHD to be reached (> 30 ng/ml). In patients with osteoporosis at risk for FIGURE 1. fracture, treatment with cholecalciferol Mean increment of absolute serum 25(OH)D level (ng/mL) at 3 months with different doses and therapeutic regimes of cholecalciferol only is not sufficient to produce a sig- (1000 IU/day, 2000 IU/day, 5000 IU/day, 100,000 IU bolus, 300,000 IU bolus, 600,000 IU bolus). For clinical indications, see nificant reduction of this risk; it must be text (from Rossini et al., 2012, mod.; Diamond et al., 2013, mod.; Giusti et al., 2010, mod.) [13, 14, 16]. associated with anti-fracture pharmaco-

28 TABLE III. Estimate of therapeutic dose (to be distributed over several weeks) and of maintenance dose of cholecalciferol based on basal 25 (OH) D concentrations (from Rossini, et al. 2016, mod.) [2]. BASAL 25OHD LEVEL CUMULATIVE THERAPEUTIC DOSE (IU) DAILY MAINTENANCE DOSE (IU) < 10 ng/mL (25 nmol/L) 600.000 2.000 10 to 20 ng/mL (25-50 nmol/L) 400.000 1.000 20 to 30 ng/mL (50-75 nmol/L) 100.000 800

logical therapy, such as antiresorptive Calcifediol um to high doses, while cholecalciferol was or osteoanabolic therapy; Calcifediol (25OHD) is the hepatic metab- administered in relatively low ones (800 • in all phase III pivotal RCTs, the active olite of vitamin D. Compared to calcitriol (a IU/day, which, as we have seen, was de- substance (bisphosphonate, denosum- biologically active metabolite), calcifediol scribed in the RCTs as the minimum effective ab or teriparatide) proved to be effec- has a higher affinity for VDBP, but a lower af- dose for fracture risk reduction) [5-9, 15, tive in reducing the risk of osteoporotic finity for VDR [4]. For this reason, calcifediol 20]. This critical difference obviously com- fracture in association with cholecalcif- must hydroxylate into its active form (calcitri- plicates the interpretation of the findings of erol; ol) in order to become biologically effective. these pharmacokinetic studies on calcifediol • vitamin D deficiency (defined as a lack Calcifediol is partially hydrophilic and is (vs. cholecalciferol) and reduces their value of cholecalciferol intake or reduced stored only in the liver and muscles [1]. It is on a clinical level. serum 25OHD) is probably the main thus unable to cause repletion of vitamin D Compared to the significant number of RCTs cause of a lack of clinical response to storage (unlike cholecalciferol). The half-life conducted on cholecalciferol to evaluate its pharmacological therapy for osteopo- of 25OHD is shorter than that of vitamin D3 effectiveness in reducing the risk of fracture, rosis (particularly in the case of antire- and has been calculated to be ca. 10-22 there have been decidedly fewer RCTs on sorptive). days [4]. This shorter half-life (with respect to calcifediol [4, 6]. A recent meta-analysis by that of cholecalciferol, which is believed to Cochrane reviewed therapeutic RCTs (inves- Ergocalciferol be of many weeks) certainly makes calcife- tigating fracture risk reduction) conducted Ergocalciferol is natural vitamin D2 of plant diol a less flexible and adaptable product with vitamin D and its metabolites: the anal- origin. It is a prohormone that requires dou- in clinical practice. Its administration/intake ysis identified only two studies on calcifediol ble hydroxylation to be transformed into its must in fact follow more rigid therapeutic re- which were deemed acceptable based on active form [1,25(OH)2D] [1]. gimes, as its shorter half-life reduces the mar- the quality of their experimental design [6]. It has been calculated that the T1/2 of circu- gins between one administration and anoth- It should be pointed out that in both of these lating ergocalciferol is ca. 48 hours, while er. It is indeed believed that a single dose studies the risk of bias was not measurable its functional half-life may be less than two is able to supply the body’s requirements [6]. On the basis of the findings of these two months [4]. Ergocalciferol is available on for no more than 12-18 days (depending studies, we can affirm that at present there the market in oral and intramuscular form. on the quantity of the dose) [1, 4]. For this is not sufficient scientific evidence to warrant For years it was believed that ergocalciferol reason, daily or weekly protocols are usu- the anti-fracture effectiveness of calcifediol and cholecalciferol were equally effective ally followed, even if it has been proposed [6, 21]. In a more recent RCT published by and were therefore interchangeable [4]. that monthly administration regimes (of high Peacock et al., for example, the incidence Recently, however, several studies have doses) are also effective [4, 6-9, 19, 20]. of new vertebral and nonvertebral fracture shown that ergocalciferol is less effective in In this context, treatment which is not regu- turned out to be similar in subjects treated increasing serum 25OHD levels than chole- larly followed over long periods of time may over four years with calcium (750 mg/day), calciferol, with an estimated ratio of 3 to 1 make patients more susceptible to the risk of calcifediol (15 μg/day) or a placebo [21]. (ergo- vs. cholecalciferol) [4, 11, 12]. hypovitaminosis D or to a lesser response to On the whole, if we wish to summarize the Few RCTs have been conducted to evalu- serum 25OHD. available evidence, we can state that in clin- ate the anti-fracture effectiveness of ergoc- Recent pharmacokinetic studies have shown ical practice calcifediol has a single advan- alciferol, either in the general population that calcifediol produces a more rapid in- tage compared to cholecalciferol: the great- or in at-risk groups, such as elderly persons crease in serum 25OHD than cholecalcif- er rapidity at which the serum 25OHD level in institutions. Overall, on the basis of the erol in subjects with vitamin D deficiency increases. In which situations this different results of these RCTs, we can affirm that er- [7-9, 19, 20]. In these studies, calcifediol pharmacokinetics is able to provide greater gocalciferol – in the experimented doses – was typically administered in doses of 20 benefits on a clinical level (e.g., reduction of has proved to be substantially ineffective in μg/day [19, 20]. Even if higher doses were the risk of fracture) has not, however, been reducing the risk of vertebral, non-vertebral also used, in daily clinical practice calcifed- clearly defined, in part given the lack of clin- and femur fracture [4, 6, 15]. iol is normally prescribed at doses between ical data from RCTs which have persuasively Based on what has been described above, 5 and 20 μg/day [4, 6-9, 19, 20]. This demonstrated its effectiveness in achieving the use of ergocalciferol in daily clinical suggests that in the pharmacokinetic studies primary endpoints. practice does seem justifiable. cited above calcifediol was used in medi- As has been recently emphasized in a liter-

29 ature review, we must, finally, keep in mind ic renal insufficiency who are being treated CONCLUSIONS the potential risk of toxicity with higher dos- with calcitriol: this recommendation is mo- In daily clinical practice, cholecalciferol es of calcifediol (Table I) [4], even if phar- tivated by the activity of extra-renal 1-α-hy- should be considered the preferred supple- macokinetic studies (20 μg/day) have not droxylase, which is not linked to feedback ment for preventing and treating vitamin D shown significant adverse events [20]. As mechanisms and is not compromised by the deficiency and for the primary and second- indicated in the guidelines, it therefore does reduced renal function; ary prevention of fragility fractures in pa- not seem appropriate to consider calcifedi- it has recently been suggested that the use of tients with osteoporosis, in association with ol a preferred drug for the prevention and calcitriol be limited to patients suffering from antiresorptive or osteoanabolic therapy. The treatment of hypovitaminosis D or in the pre- chronic renal insufficiency with low cardio- use of other vitamin D metabolites – calcifed- vention of fragility fractures in patients with vascular risk profiles. iol, alfacalcidol and calcitriol in particular – osteoporosis, in association with antiresorp- should be limited to specific situations, such tive or osteoanabolic medication. [1, 2]. It Alfacalcidol as conditions of chronic renal insufficiency is, by contrast, necessary to emphasize that Alfacalcidol, or 1-α-hydroxy-vitamin D, is or hypoparathyroidism (alfacalcidol and calcifediol represents the chosen vitamin D a prodrug which requires 25-hydroxylation calcitriol), malabsorption syndrome, severe metabolite in treating patients with chronic in the liver to become metabolically active obesity or hepatic insufficiency (calcifediol). liver disease and severe reduction of the he- [1,25(OH)2D]. It was first synthesized in the These recommended restrictions concerning patic function. early 1970’s and used clinically beginning the use of vitamin D metabolites are mainly in 1973, with the aim of administering a due to the limited evidence proving their ef- Calcitriol prohormone that was able to bypass renal fectiveness in reducing the risk of fracture, Calcitriol [1,25(OH)2D] is the active me- 1-α-hydroxylation and that would thus be us- the lack of appropriate studies that directly tabolite of vitamin D and the natural ligand able even in the presence of reduced renal “pit” them against cholecalciferol, and the of VDR. It has a short half-life, calculated at function [4, 20]. Alfacalcidol therefore rep- potential risk of adverse events linked to ca. 5-8 hours [4]. For this reason it must be resents an alternative to calcitriol. their hypercalcemizing action (especially for administered daily (in some studies it is also For a certain period, the use of alfacalcid- 1-α-hydroxylated metabolites). used with intermittent regimes) and sometimes ol in clinical practice was strongly encour- in lower doses distributed over a 24-hour pe- aged. It was indeed believed that because riod [4, 6, 20]. Administered doses usually alfacalcidol needs to be activated (25-hy- References range from 0.25 to 1 μg/day [4, 6]. droxylation) its pharmacokinetics was pref- 1 Adami S, Romagnoli E, Carnevale V, et Since its discovery in the 1970’s, calcitriol erable to that of calcitriol, as its action is al. Guidelines on prevention and treatment has been successfully used in treating sec- more enduring (because of its longer half- of vitamin D deficiency. Italian Society for ondary hyperparathyroidism in patients af- life) and it creates less exposure to the risk Osteoporosis, Mineral Metabolism and fected with chronic renal insufficiency, or in of hypercalcemia [4, 20]. This theoretical Bone Diseases (SIOMMMS). Reumatismo the prevention of hypocalcemia in patients advantage, however, has not been realized 2011;63:129-47. suffering from hyperparathyroidism [4, 20]. in clinical practice. 2 Rossini M, Adami S, Bertoldo F, et al. More recently, calcitriol has been used and Although slightly longer than that of calcitri- Guidelines for the diagnosis, prevention studied in RCTs aimed at evaluating its ef- ol, the half-life of alfacalcidol is ca. 12 hours and management of osteoporosis. Reumat- fectiveness in reducing fracture risk [6, 20]. (the time necessary for its total metabolic ismo. 2016;68:1-39. In some – though not all – of these RCTs, conversion) [4]. For this reason, alfacalcidol 3 Autier P, Boniol M, Pizot C, et al. Vita- calcitriol has been shown to reduce the risk must also be administered daily. It has been min D status and ill health: a systemat- of fracture [4, 6, 20]. Nonetheless, these calculated that a daily dose of 1 μg of al- ic review. Lancet Diabetes Endocrinol same RCTs have also reported a greater facalcidol is the bioequivalent of 0.5 μg of 2014;2:76-89. and more significant incidence of adverse calcitriol [20]. Administered doses typically 4 Mazzaferro S, Goldsmith D, Larsson TE, et events, such as hypercalcemia, hypercalci- range from 1 to 5 μg/day [4, 6]. al. Vitamin D metabolites and/or analogs: uria and nephrolithiasis in subjects treated As in the case of calcitriol, alfacalcidol is which D for which patient? Curr Vasc Phar- with calcitriol [4, 6, 20]. generally recommended for use in patients macol 2014;12:339-49. Because of the lesser degree of safety and affected by chronic renal insufficiency [4, 5 Bischoff-Ferrari HA, Willett WC, Orav EJ, clinical practicality of calcitriol, the interna- 20]. et al. A pooled analysis of vitamin D dose tional scientific community agrees that its use In some RCTs (and meta-analyses), alfacal- requirements for fracture prevention. N should be limited to patients suffering from cidol has been shown to significantly re- Engl J Med 2012;367:40-9. chronic renal insufficiency or to patients af- duce the incidence of new fractures [4, 6, 6 Avenell A, Mak JC, O’Connell D. Vitamin fected by hypoparathyroidism [2, 4, 20]. 20]. As with calcitriol, though, prolonged D and vitamin D analogues for preventing In the context of treating patients suffering treatment with alfacalcidol can expose pa- fractures in post-menopausal women and from chronic renal insufficiency, two other tients to a heightened risk of adverse events older men. Cochrane Database Syst Rev aspects of the use of calcitriol should be linked to its hypercalcemizing action. For 2014;(4):CD000227. mentioned [4, 10]: this reason, the use of alfacalcidol in clini- 7 Meyer O, Dawson-Hughes B, Sidelnikov E, numerous writers and opinion leaders pro- cal contexts should be subject to the same et al. Calcifediol versus vitamin D3 effects pose the contemporary administration of guidelines and limitations as those for cal- on gait speed and trunk sway in young cholecalciferol in patients affected by chron- citriol [4]. postmenopausal women: a double-blind

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