Vitamin D: are all compounds equal?

ABSTRACT

Vitamin D is a pre-hormone essential for maintaining mineral homeostasis and also plays significant roles in bone, cardiovascular and renal health. Vitamin D deficiency is prevalent in the general population, and even more so in chronic kidney disease (CKD) patients, in which it contributes to the development and progression of mineral and bone disorder. The landscape of vitamin D treatment has evolved, with several analogues now available, each possessing distinct pharmacokinetic and pharmacodynamic properties, efficacies and safety profiles. This diversity allows for tailored, personalized approaches to treatment in CKD patients. This review aims to provide a comprehensive overview of vitamin D, including its natural sources and metabolism, and examines the main available pharmacological vitamin D products. Particular emphasis is placed on their application in CKD management, highlighting how these compounds can be strategically used to address both vitamin D deficiency and secondary hyperparathyroidism, while also acknowledging the ongoing debate about their impact on bone health and other clinical outcomes.

INTRODUCTION

Vitamin D was first identified at the beginning of the 20th century as the deficient factor responsible for rickets [1]. Despite its name, it is not technically a vitamin, but rather a fat-soluble hormone that can be synthesized by the human body [2]. It exerts its biological actions by binding to the intracellular vitamin D receptor (VDR), which acts as a transcription factor, regulating the expression of numerous vitamin D–responsive genes [3]. The primary function of vitamin D is regulating mineral homeostasis. Specifically, it increases calcium and phosphorus absorption in the intestine and kidney [4], stimulates osteoclastogenesis and bone resorption [5] and modulates the expression of parathyroid hormone (PTH) [6] and calcium-sensing receptor [7] in the parathyroid glands. Beyond these ‘traditional’ functions related to mineral homeostasis, vitamin D is involved in antiproliferative, prodifferentiative and immunomodulatory activities [8], protective mechanisms against atherosclerosis, thrombosis and cardiac hypertrophy [9], as well as renin–angiotensin–aldosterone system regulation [10].

Vitamin D deficiency is prevalent among patients with chronic kidney disease (CKD) [11] and contributes to the pathophysiology of mineral and bone disorder (MBD) [12], a systemic condition characterized by abnormal metabolism of calcium, phosphate, parathyroid hormone and vitamin D, which leads to bone and cardiovascular (CV) disease [13].

This review provides an overview of vitamin D's natural sources and metabolism and outlines the main pharmacological sources of vitamin D and their properties, indications, efficacies and safety, with a particular focus on CKD patients.

NATURAL SOURCES AND METABOLISM

The human body primarily uses two forms of vitamin D: vitamin D3 and vitamin D2. Vitamin D3 synthesis in the skin, following sunlight exposure, is the most important source of vitamin D in humans (Fig. 1). Therefore, seasonal fluctuations in vitamin D levels are common, depending on the amount of sunlight exposure [14]. In cases of limited sun exposure, adequate dietary intake can compensate for the lack of synthesized vitamin D. Dietary vitamin D3 can be found in fish, cheese and egg yolks, while vitamin D2 is present in mushrooms and yeast. In many countries where these foods are not commonly consumed, vitamin D–fortified foods such as milk, butter and cereals have been introduced. Notably, the absorption of dietary vitamin D occurs primarily in the duodenum and requires bile salts [15].

Both vitamin D3 and D2 are biologically inert and require two hydroxylations to become biologically active as 1,25-dihydroxyvitamin D [1,25(OH)₂D]. The first hydroxylation occurs in the liver, where vitamin D2 and D3 are converted into 25-hydroxyvitamin D [25(OH)D] by the mitochondrial hydroxylase CYP27A1 and the microsomal hydroxylase CYP2R1. The activity of these 25(OH)-hydroxylases is induced, rather than inhibited, by the available substrate, making 25(OH)D levels highly dependent on vitamin D production or intake and significantly more stable than 1,25(OH)₂D levels. Thus the serum 25(OH)D level is the currently preferred indicator of vitamin D status in the body [16]. Commercially available assays for its determination should adhere to current analytical standards and be traceable by the Vitamin D Standarization Program [17].

The second hydroxylation mainly occurs in the kidney and, to a lesser extent, in other tissues, including the prostate, breast, colon, lung, parathyroid, pancreatic β cells and monocytes [18]. In the kidney, 25(OH)D is activated by the mitochondrial enzyme CYP27B1, whose activity is induced by PTH and inhibited by fibroblast growth factor 23 (FGF23) and 1,25(OH)₂D [19]. Under physiological conditions, 1,25(OH)₂D produced in the kidneys exerts systemic functions, whereas that produced by 1α-hydroxylases expressed by peripheral cells acts as an autocrine or paracrine factor. However, in specific conditions such as pregnancy, CKD, granulomatous disorders and rheumatoid arthritis, extrarenal production of 1,25(OH)₂D may increase, contributing to the systemic pool [18, 20].

In target tissues, 1,25(OH)₂D is inactivated by the 24-hydroxylase CYP24A1¹⁸, which is regulated oppositely to 1α-hydroxylase, being induced by phosphate [21], FGF23 and 1,25(OH)₂D [22] and inhibited by PTH. Additionally, increased VDR activation by 1,25(OH)₂D stimulates the catabolism of 25(OH)D to 24,25-dihydroxyvitamin D [24,25(OH)₂D] as a protective homeostatic mechanism against vitamin D toxicity [23].

Both 25(OH)D and 1,25(OH)₂D are primarily transported in plasma by vitamin D binding protein (DBP) [24], and to a lesser extent by albumin, with only 1% of total serum vitamin D being free. Notably, DBP-bound vitamin D is not bioavailable [25], making it challenging to ascertain true bioavailability from total 25(OH)D levels alone, especially considering the significant variability in both DBP levels and binding affinity among individuals [26, 27]. Consequently, emerging research has proposed the vitamin D metabolite ratio (VMR), defined as the ratio of 24,25(OH)₂D to 25(OH)D, as a potentially superior indicator of vitamin D status that remains unaffected by DBP concentrations and genotypic variations [28].

Lastly, epimeric metabolites of vitamin D have also been identified, resulting from a change in the orientation of the C3 hydroxy group [29]. These include 3-epi-25(OH)D, 3-epi-1,25(OH)₂D₃ and 3-epi-24,25(OH)₂D₃. Although the enzyme responsible for the epimerization process, as well as the conditions favouring this conversion, have yet to be fully elucidated, these forms can constitute up to half of the total concentrations of vitamin D metabolites [30], potentially influencing the end-organ effects and clinical interpretation of vitamin D status. However, more research is necessary to fully understand their biological activity, regulation and implications for health.

VITAMIN D DEFICIENCY AND CKD-MBD

There is no consensus on the definition of vitamin D insufficiency and deficiency. The Endocrine Society defines a 25(OH)D level of 21–29 ng/ml (51–74 nmol/l) as insufficient and <20 ng/ml (50 nmol/l) as deficient, whereas the Institutes of Medicine uses 20 and 12 ng/ml as thresholds for insufficiency and deficiency, respectively [31]. In the general population, these conditions are extremely common, with an estimated prevalence of 88% worldwide [32].

Compared with the general population, CKD patients have increased risks of 25(OH)D and 1,25(OH)₂D deficiencies and vitamin D hyporesponsiveness. The higher prevalence of 25(OH)D deficiency in CKD patients [11, 33–35] can be attributed to several factors, including decreased nutritional intake due to dietary restrictions, impaired photoproduction caused by uraemic toxins (including FGF23-mediated catabolism), dermopathy or limited sun exposure due to their frail condition and indoor lifestyle and low DBP levels in patients with proteinuric nephropathies or undergoing peritoneal dialysis. Additionally, in CKD patients, 1α-hydroxylase levels may be reduced due to compromised kidney structure, and its activity may be suppressed by hyperphosphataemia and elevated FGF23 levels. This often leads to a higher incidence of 1,25(OH)₂D deficiency independent of 25(OH)D levels, although increased compensatory activity of the extrarenal 1α-hydroxylases may mitigate this condition [36]. For instance, microinflammation may be responsible for increased extrarenal CYP27B1 activity in CKD patients [37].

In the context of CKD-MBD (Fig. 2), vitamin D deficiency contributes to the development of hypocalcaemia, hyperparathyroidism and bone disorders. Specifically, low 1,25(OH)₂D levels reduce intestinal calcium absorption [4], leading to hypocalcaemia and a subsequent compensatory increase in PTH, known as secondary hyperparathyroidism (SHPT). Moreover, low levels of 1,25(OH)₂D directly induce PTH transcription [6] and reduce the number of VDRs in the parathyroid glands [38], promoting cell hyperplasia and nodule formation [39]. Finally, prolonged vitamin D deficiency impacts bone formation and mineralization [40, 41], resulting in osteomalacia, osteoporosis and an increased risk of fractures.

PHARMACOLOGICAL COMPOUNDS

The first vitamin D drugs (known as vitamin D analogues) were approved in the late 1960s [1], and several vitamin D analogues have entered the market since then. Ergocalciferol (D₂), cholecalciferol (D₃) and calcifediol [25(OH)D₃] are nutritional forms of vitamin D approved as supplements to treat vitamin D deficiency. Moreover, they can be used for empiric supplementation in individuals ages 1–18 years or ≥75 years, pregnant women and patients with high-risk prediabetes [42]. Calcitriol, alfacalcidol, doxercalciferol, paricalcitol, falecalcitriol and maxacalcidol are active vitamin D metabolites that are approved to treat CKD-MBD and bone diseases. This section provides a summary of the main characteristics of the currently available vitamin D analogues, as presented in Table 1. Falecalcitriol and maxacalcidol are available only in Japan and will not be discussed in this review.

Prodrugs

Ergocalciferol and cholecalciferol are lipophilic compounds that, in the presence of bile acids, are rapidly absorbed from the gut and subsequently stored in adipose tissue. This allows for a slow turnover rate, making them suitable for administration in high intermittent doses (weekly, fortnightly or even monthly), which can improve patient compliance and adherence to treatment. The main difference between the two calciferols is the lower affinity of ergocalciferol for the DBP compared with cholecalciferol, resulting in a shorter circulating half-life and lower potency [43]. Moreover, they have different geographic distributions: ergocalciferol is the most common prodrug used in the USA and Canada, while its use is rare in Europe, where cholecalciferol is more extensively used. The metabolic conversion of both prodrugs to 25(OH)D may vary based on the serum level of 25(OH)D [44], as well as age- and disease-related decreases in hepatic 25-hydroxylase activity. Thus these compounds may not be efficient in replenishing 25(OH)D levels in patients with advanced liver disease or those receiving drugs that interfere with hepatic hydroxylases (e.g. antiepileptic, anticancer and antiretroviral drugs) [45], where the use of calcifediol is preferable.

Calcifediol

Compared with ergocalciferol and cholecalciferol, calcifediol is more hydrophilic. This allows for higher absorption in the gut, independent of bile function, making it a better supplement for patients with malabsorptive gastrointestinal diseases [15, 46] and those with previous bariatric surgery. On the other hand, its lower lipophilicity prevents storage in adipose tissue, resulting in a shorter half-life compared with calciferols. This means that small daily doses, rather than high intermittent doses, are required to adequately replenish vitamin D levels. Calcifediol has a linear and predictable dose–response curve, irrespective of serum 25(OH)D concentrations and hepatic 25-hydroxylase activity [44]. Thus it should be preferred over prodrugs in situations where a rapid increase in 25(OH)D levels is required, such as in patients with severe symptoms of osteomalacia or before initiation of an antiresorptive treatment [47].

Another relevant difference between calcifediol and prodrugs is their affinity for VDRs. While ergocalciferol and cholecalciferol are inactive compounds, calcifediol can weakly bind to VDRs and activate them [48]. Possibly through this mechanism, calcifediol is able not only to replenish vitamin D levels, but also to reduce PTH levels, and is therefore indicated for treatment of SHPT in CKD patients [49]. Calcifediol is currently available in traditional immediate-release formulations and in the more recent extended-release formulation (ERC), approved in the USA, Canada and Europe [50]. ERC is formulated as calcifediol monohydrate in a lipophilic excipient mixture that provides extended release over a 12-hour period. This allows for a gradual increase in 25(OH)D levels, while avoiding triggering the upregulation of FGF23 and vitamin D catabolism through CYP24A1 [51].

Active forms

Unlike nutritional forms of vitamin D, calcitriol, alfacalcidol, doxercalciferol and paricalcitol do not require hydroxylation in the kidneys, as they are either already active or undergo rapid activation in the liver. This property makes these active compounds effective even in patients with advanced stages of CKD, who may have low 1α-hydroxylase activity. Consequently, they are a cornerstone of CKD-MBD treatment, and current international guidelines recommend the use of active vitamin D analogues for treating SHPT in patients with end-stage kidney disease receiving dialysis. Conversely, the same guidelines suggest that they should not be routinely used in patients with earlier stages of CKD (those not on dialysis), except in cases of severe and progressive SHPT [13]. However, this point has been long debated, and some have suggested that a low dose of active vitamin D could be a helpful supplement to nutritional vitamin D and dietary phosphate restriction in treating SHPT, without waiting for a severe and progressive form to be present [52, 53].

In addition to CKD-MBD, calcitriol and alfacalcidol are used to treat osteoporosis, osteomalacia and several forms of hypocalcaemia, including neonatal, postoperative and those due to hypoparathyroidism or pseudohypoparathyroidism. In fact, these treatments increase intestinal calcium absorption, which raises serum calcium levels but may also lead to hypercalcaemia. Along with calcium, phosphate absorption is also enhanced, increasing the risk of hyperphosphataemia, especially in patients with impaired kidney function.

To overcome these common side effects, other agents have been developed specifically for the treatment of CKD-MBD. Doxercalciferol consists of 1α(OH)D₂, which needs to be hydroxylated and activated in the liver. This characteristic should allow for more controlled release and activation, potentially leading to a more balanced effect on mineral metabolism and a less pronounced effect on calcium and phosphate absorption [54]. However, doxercalciferol should be administered with caution in patients with hepatic impairment [55]. Paricalcitol has been designed to have a higher affinity for VDRs in the parathyroid glands and kidneys compared with the intestinal receptors.

CLINICAL EFFICACY AND SAFETY OF VITAMIN D ANALOGUES IN CKD PATIENTS

Treatment of vitamin D deficiency

For CKD patients, current international guidelines suggest measuring 25(OH)D levels and addressing vitamin D deficiency using treatment strategies recommended for the general population [13]. For adult patients, this involves treating with 800–2000 IU/day of cholecalciferol or ergocalciferol or 5–10 μg/day of calcifediol, based on the patient's body weight, age and sun exposure [31, 56, 57]. The efficacy of these therapies in CKD patients has been tested in several randomized controlled trials (RCTs), outlined in Table 2 and summarized in this section.

Various dosing regimens of orally administered cholecalciferol have been proven effective in treating vitamin D deficiency in patients with mild–moderate CKD [58–67], end-stage kidney disease receiving dialysis [68–77] and kidney transplant recipients (KTRs) [78, 79]. Beyond improving 25(OH)D levels, cholecalciferol treatment has been shown to increase 1,25(OH)₂D levels [62, 64, 65, 69–73, 76, 78, 79], even in dialysis patients, likely due to extrarenal 1α-hydroxylase activity.

Ergocalciferol is another effective supplement for treating vitamin D deficiency in CKD patients, both on dialysis [80, 81] and not [67, 82–84]. However, its efficacy appears to be lower than that of cholecalciferol. This is likely because supplementation with vitamin D₂ increases serum levels of 25(OH)D₂ but simultaneously reduces 25(OH)D₃ levels, resulting in a less robust increase in total 25(OH)D, as previously reported in healthy individuals [43, 85, 86]. Additionally, ergocalciferol's shorter circulating half-life may result in a reduced capacity to maintain sufficient 25(OH)D levels in the long term [43]. A head-to-head comparison between the two calciferols in CKD patients was made in a small RCT by Wetmore et al. [87], who randomized 41 adult patients with CKD stages 3–5 not on dialysis and 25(OH)D levels <30 ng/ml to receive either 50 000 IU/week of cholecalciferol or ergocalciferol for 12 weeks. Treatment with cholecalciferol resulted in a greater increase in 25(OH)D levels compared with ergocalciferol (45 ± 16.5 ng/ml from baseline versus 30.7 ± 15.3 ng/ml, respectively; P < .01). However, this difference may not be clinically relevant, as the active form 1,25(OH)₂D showed similar increases with both treatments (4.8 ± 14.7 pg/ml with cholecalciferol and 4.9 ± 12.2 ng/ml with ergocalciferol). Thus both drugs are suitable for treating vitamin D deficiency in CKD patients, although ergocalciferol likely requires higher doses.

To date, calcifediol has been proven effective in replenishing 25(OH)D levels in the general population [88, 89], and its use rather than calciferols is indicated in cases of obesity, malabsorption syndromes, advanced liver disease, concomitant use of glucocorticoids or inhibitors of hepatic 25-hydroxylase activity and when rapid correction of vitamin D deficiency is required [57]. Although there are no RCTs investigating its superiority to cholecalciferol or ergocalciferol in treating vitamin D deficiency specifically in CKD patients, calcifediol may be advantageous in this population. In fact, as CKD progresses, vitamin D deficiency is often accompanied by SHPT, and calcifediol, especially ERC, is an effective option for treating both conditions, as described in the next section.

Treatment of SHPT

Vitamin D analogues are a key component of SHPT treatment in CKD, alongside phosphate-lowering drugs and calcimimetics [90], as they reduce PTH secretion and inhibit cell hyperplasia [6, 39] through VDR activation in the parathyroid glands. However, it is still uncertain if reducing PTH levels improves clinical outcomes and what the optimal target level for PTH should be, especially in patients not on dialysis. As previously mentioned, current guidelines suggest that vitamin D analogues should not be routinely used to treat SHPT in patients with CKD stages 3–5 not on dialysis, unless in severe and progressive cases. Conversely, their use is suggested to lower PTH levels to the range of ≈2–9 times the upper normal limit for the assay in dialysis-dependent CKD patients [13].

Most RCTs involving cholecalciferol and ergocalciferol in CKD patients (Table 2) have failed to demonstrate a considerable reduction in PTH levels [58–60, 62, 63, 65–72, 76, 77, 79, 80, 82–84, 87]. However, there are some exceptions. For instance, a meta-analysis of five RCTs showed that doses of cholecalciferol ranging from 20 000 IU once a week to 25 000 IU once a month reduced PTH over time with a significant, although small, difference in final PTH levels between treated patients and controls {mean difference −32 pg/ml [95% confidence interval (CI) −57.0 to −6.1]} [91]. Later, patients with CKD stages 2–5 treated with cholecalciferol 50 000 IU/week for 12 weeks followed by 50 000 IU fortnightly for 40 weeks showed a mild but significant reduction in PTH levels after the initial treatment phase (89 ± 49 to 70 ± 25 pg/ml; P = .01), but this effect was not sustained during the maintenance phase, despite sufficient 25(OH)D levels [61]. Similarly, in haemodialysis patients, a single high dose of cholecalciferol (180 000 IU) reduced PTH levels at 2 weeks (from 302 ± 154 to 218 ± 129 pg/ml; P < .001), but this effect was not sustained over the following 14 weeks of follow-up [73], suggesting that frequent high doses would be required for effective treatment of SHPT. This was confirmed by Nata et al. [81], who demonstrated that a double dose of ergocalciferol (100 000 IU/week) effectively reduced PTH in a Thai cohort of haemodialysis patients, whereas the conventional dose of 50 000 IU/week did not. Thus prodrugs alone are not indicated for the treatment of SHPT but may be used in combination with active compounds and/or calcimimetics to achieve additional PTH reductions [74, 75], potentially allowing for lower doses of active vitamin D.

Among nutritional forms of vitamin D, ERC is able to consistently reduce PTH and is therefore indicated for the treatment of both vitamin D deficiency and SHPT in CKD patients. Different dosing regimens have been shown to effectively increase 25(OH)D and 1,25(OH)₂D levels and reduce PTH levels in a dose-dependent manner in patients with CKD stages 2–3 treated for 6 weeks [92]. These findings were confirmed in two larger RCTs in patients with CKD stages 3–4 with longer treatment duration (up to 52 weeks) [93]. In the pooled population of the two studies, 50% of patients treated with ERC achieved a ≥30% reduction in PTH levels, compared with <8% of individuals treated with placebo (P < .001). Notably, there were no differences in FGF23 trajectories between active treatment and placebo, whereas the use of active vitamin D metabolites is often complicated by increased FGF23 levels [50].

Among active compounds, calcitriol and alfacalcidol have been used to treat SHPT since the late 1980s [94, 95]. They have been proven effective in reducing PTH levels in dialysis patients [94–97] and in patients with earlier stages of CKD [98–100] (Table 3). Their efficacy is similar whether administered orally or intravenously [101–106] and whether dosed daily or intermittently (1–3 times per week) [105, 107–110]. When compared with one another, alfacalcidol requires a 1.5- to 2-fold higher dose than calcitriol to achieve similar results [111]. Besides reducing PTH levels, both compounds have frequently increased calcium and phosphate levels, heightening the risk of hypercalcaemia and hyperphosphataemia, which may require dose reduction. Notably, only a low dose of calcitriol (0.125 μg/day) avoided this complication in the above-referenced RCTs [98].

Doxercalciferol, introduced in the 2000s, was expected to have a less pronounced effect on calcium and phosphate balance; however, there are no RCTs comparing doxercalciferol with calcitriol or alfacalcidol in SHPT patients to assess its relative safety. Two placebo-controlled RCTs in CKD patients [54, 112] have demonstrated its efficacy in treating SHPT, although with a non-negligible effect on calcium and phosphate. In 138 dialysis patients with SHPT treated with 10 μg of oral doxercalciferol thrice weekly for 16 weeks, PTH levels were reduced by 56 ± 3% (from a baseline of 897 ± 52 pg/ml), but serum calcium increased from 9.2 ± 0.8 to 9.7 ± 1.1 mg/dl (P < .001) and serum phosphate from 5.4 ± 1.1 to 5.9 ± 1.6 mg/dl (P < .001) [54]. When patients were randomized to continue doxercalciferol or switch to placebo for an additional 8 weeks, calcium and phosphate levels remained stable with doxercalciferol and decreased with placebo. Patients continuing doxercalciferol had significantly higher rates of hypercalcaemia (3.3% versus 0.5%; P < .01) and hyperphosphataemia (7.1% versus 2.3%; P < .01) compared with those receiving placebo. However, these side effects could be attributed to the high dose used, as lower doses of doxercalciferol (1 μg/day, titrated up to a maximum of 5 μg/day) successfully reduced PTH levels (from 219 ± 22 to 118 ± 17 pg/ml) in patients with CKD stages 3–4 and SHPT over 24 weeks without significant differences in hypercalcaemia or hyperphosphataemia rates compared with placebo [112].

Finally, various dosing regimens of oral and intravenous paricalcitol have been proven effective in reducing abnormal PTH levels in both non-dialysis-dependent [113, 114] and dialysis-dependent [115–119] CKD patients, as well as KTRs [120, 121]. Head-to-head comparisons with calcitriol and alfacalcidol have shown that paricalcitol has a similar efficacy [122–128], with a comparable suppressive effect when dosed at a 3:1 ratio (e.g. 3 μg of paricalcitol equals 1 μg of calcitriol or alfacalcidol). To achieve similar effects on PTH, the relative dose of doxercalciferol needed is 55–60% of the paricalcitol dose [129]. Unfortunately, most studies have shown similar effects of these drugs on calcium and phosphate levels [123–127, 129], with only a few exceptions. First, Sprague et al. [122] reported that haemodialysis patients randomized to paricalcitol had a lower rate of hypercalcaemia compared with those treated with calcitriol (18% versus 33%; P = .008). Second, Večerić-Haler et al. [128] found that both paricalcitol and calcitriol increased serum calcium in the first week of treatment, but calcium levels subsequently decreased with paricalcitol while remaining elevated with calcitriol. Thus, further studies are needed to clarify whether paricalcitol truly has a lower calcaemic effect compared with other vitamin D analogues.

Treatment of bone disease

For CKD patients, as with the general population, the treatment of osteopenia and osteoporosis encompasses non-pharmacological and pharmacological interventions, beginning with ensuring adequate calcium and vitamin D intake [130, 131]. With this recommended intake, there is no clear evidence of additional benefits of vitamin D supplementation on bone outcomes specifically in CKD patients [132, 133]. Indeed, the use of active forms of vitamin D can increase bone mineral density in CKD patients [94, 99, 121, 134–138], but these compounds also significantly reduce biomarkers of bone turnover and may heighten the risk of PTH oversuppression in patients who already have PTH hyporesponsiveness [139]. Overall, a recent meta-analysis of 128 RCTs including 11 270 CKD patients (stages 3–5) demonstrated an uncertain effect of vitamin D supplementation on fracture risk [relative risk (RR) 0.68 (95% CI 0.37–1.23)] [140]. However, this meta-analysis did not include KTRs, in which cholecalciferol supplementation seemed effective in attenuating BMD loss [141] and reducing fracture risk [142].

Effect on proteinuria and CKD progression

Some evidence suggests that vitamin D analogues might slow down CKD progression [143]. This could be mediated by a reduction in PTH [144] or attributed to an antiproteinuric effect. This was first demonstrated in 2005, when the pooled results of three RCTs showed that 50% of patients with CKD stages 3–4 and proteinuria treated with oral paricalcitol experienced a reduction in proteinuria, compared with 25% of patients treated with placebo [145]. Another RCT later confirmed that paricalcitol lowered residual albuminuria (16% decrease in urinary albumin:creatinine ratio, compared with −3% in the placebo group) in patients with diabetic nephropathy who were receiving inhibitors of the renin–angiotensin–aldosterone system [146]. However, although this antiproteinuric property of paricalcitol has been described by other RCTs [147–149], an effect on CKD progression has not yet been proven. Thus the use of active vitamin D analogues solely for the purpose of reducing proteinuria is not recommended, as their potential nephroprotective effect could be counterbalanced by the risk of unwanted positive calcium balance [150] and increased synthesis of FGF23 [151].

Efficacy of vitamin D analogues on other outcomes

Although observational studies have shown associations between vitamin D deficiency and increased risk of cancer [152], CV disease [153] and mortality [154], large RCTs comparing vitamin D supplementation with placebo have generally failed to demonstrate benefits for clinical outcomes, even though they significantly increased 25(OH)D levels [133, 155]. For instance, the randomized, placebo-controlled VITAL study (NCT01169259) failed to show an effect of cholecalciferol supplementation on the incidence of cancer or CV events in >25 000 healthy individuals [156]. Similarly, in the randomized, double-blind, placebo-controlled D-Health trial (ACTRN12613000743763), the administration of cholecalciferol with a monthly dose to >20 000 unscreened Australian individuals ≥60 years of age did not reduce all-cause, CV or cancer-related mortality [157]. Although subgroup analyses have not identified any effect modification based on baseline 25(OH)D concentrations, the presence of CKD or its stage, it should be noted that these trials may lack sufficient power to adequately evaluate these subgroups and that 25(OH)D may not be the most reliable biomarker for assessing vitamin D status. Nonetheless, their findings do not support widespread vitamin D supplementation in unselected healthy individuals.

In CKD patients, few RCTs have aimed to clarify the CV effects of vitamin D analogues, but whether their use may prevent CV complications remains unclear. The PRIMO (NCT00497146) [158] and OPERA (NCT00796679) [159] placebo-controlled trials investigated the effect of paricalcitol on left ventricular mass in CKD patients with cardiac hypertrophy. Of note, these studies focused on CV endpoints and were not specifically targeted at PTH control, with high doses of paricalcitol used to treat mild–moderate SHPT. Although in both trials paricalcitol failed to reduce cardiac hypertrophy, patients treated with paricalcitol had lower rates of CV-related hospitalizations compared with those receiving placebo (1.1 versus 8.8/100 person-years in the PRIMO trial and 0% versus 17% of patients in the OPERA trial). Conversely, CV events were not reduced by alfacalcidol [160] or calcifediol [161] in two cohorts of dialysis patients. However, these results should be interpreted with caution, as the control groups in these RCTs consisted of patients receiving ‘standard care’, including other vitamin D analogues or calcimimetics, rather than a placebo. The recent meta-analysis by Yeung et al. [140] confirmed an uncertain effect of vitamin D supplementation on CV outcomes [with a RR for death due to CV causes of 0.73 (95% CI 0.31–1.71)]. The effect of vitamin D analogues on other CV outcomes, such as arterial stiffness and endothelial dysfunction, remains unclear, as many small RCTs over the last decade have shown conflicting results [64, 162–168], highlighting the need for further research.

CONCLUSIONS

Vitamin D deficiency is highly prevalent among CKD patients and significantly contributes to the development of CKD-MBD, making vitamin D analogues essential in the management of this population. The availability of various vitamin D pharmacological compounds, each with distinct pharmacokinetic and pharmacodynamic, efficacy and safety profiles, theoretically enables a personalized approach to treatment. All nutritional forms of vitamin D are effective in safely ensuring adequate vitamin D intake and treating vitamin D deficiency. Recently, ERC has been developed to treat SHPT, while replenishing vitamin D levels. Active vitamin D is a potent treatment for SHPT and may offer additional benefits, including potential improvements in CV outcomes and reductions in proteinuria. Nevertheless, the use of active agents must be carefully monitored due to the risks of hypercalcaemia, hyperphosphataemia, elevated FGF23 levels and excessive PTH suppression. While the use of active vitamin D metabolites in dialysis patients is universally accepted, their use in earlier stages of CKD remains debated. The upcoming Kidney Disease: Improving Global Outcomes controversies conference on CKD-MBD and European Renal Osteodystrophy consensus paper on vitamin D supplementation in CKD will likely provide more guidance on this matter.

Thus the question posed in the title of this review, ‘Vitamin D: are all compounds equal?’, cannot be definitively answered due to the lack of head-to-head clinical comparisons, especially in CKD patients. Current evidence does not provide enough data to draw robust conclusions on the clinical relevance of pharmacokinetic and pharmacodynamic differences between vitamin D compounds. This lack of direct comparative data limits the ability to fully personalize treatment. Although some inferences can be made regarding the potential advantages or risks of different compounds, as discussed in this review, comprehensive clinical trials are needed to address these gaps in knowledge.

FUNDING

This article was published as part of a supplement financially supported by an educational grant from CSL Vifor.

AUTHORS’ CONTRIBUTIONS

L.M. was responsible for the literature search, conceptualization and writing the original draft. M.Cassia and A.G. were responsible for the literature search and review of the manuscript draft. P.C. was responsible for review of the manuscript draft. J.B. and M.Cozzolino were responsible for conceptualization, supervision and review.

DATA AVAILABILITY STATEMENT

No new data were generated or analysed in support of this research.

CONFLICT OF INTEREST STATEMENT

A.G. declares receipt of advisory board, lecture fees and/or travel support from Amgen and CSL Vifor. J.B. declares receipt of advisory board, lecture fees and/or travel support from Amgen, AbbVie, Sanofi, CSL Vifor, AstraZeneca, Rubió, Menarini and Bayer. M.Cozzolino declares receipt of advisory board, lecture fees and/or travel support from Amgen and CSL Vifor.

REFERENCES