Calcifediol: Efficacy, Safety & Clinical Applications

Calcifediol is an active metabolite of vitamin D used to treat hyperparathyroidism as well as to combat hypocalcemia in dialysis patients. It is used to treat secondary hyperparathyroidism (a condition in which the body produces too much parathyroid hormone [PTH; a natural substance needed to control the amount of calcium in the blood], ) in certain adults with chronic kidney disease (condition in which the kidneys stop working slowly and gradually). Calcifediol is in a class of medications called vitamin D analogs. It works by helping the body to use more of the calcium found in foods or supplements and by regulating the body's production of parathyroid hormone.

Cholecalciferol or Calcifediol in the Management of Vitamin D Deficiency

At present, vitamin D deficiency, in some cases even severe, is significantly prevalent worldwide. From the enormous amount of scientific literature that supports the above, we would highlight the extensive review of epidemiological studies on vitamin D status conducted in Europe, South America, North America, Asia and Oceania published by Hilger J et al. in 2014, which estimated that 88.1% of the world’s population would have levels of 25(OH)D (25-hydroxy-vitamin D, also called calcidiol or calcifediol, a metabolite determined in plasma as a biomarker of vitamin D status) below 30 nanograms/milliliter (ng/mL) (minimum level of 25-hydroxy-vitamin D considered optimal with a certain degree of consensus). On the other hand, the other alternative for exogenous supplementation, calcifediol, is the result of the hydroxylation of cholecalciferol in its carbon 25 position, forming 25-hydroxy-vitamin D3, a molecule known as calcifediol or calcidiol. In conclusion, due to all the genetic and environmental factors previously exposed, there is a clear need for exogenous therapeutic vitamin D supplementation in an increasing proportion of patients, and from a medical point of view, it is relevant to evaluate the different available therapeutic options in order to select the most appropriate one in accordance with the highest level of achieved scientific evidence.[1]

The causes of this disparity in clinical results obtained between the two molecules could go beyond the mere difference in availability of cholecalciferol and calcifediol to conduct clinical research worldwide and really respond to relevant pharmacokinetic and pharmacodynamic differences between the two substances assessed as prescription drugs. Although these aspects will be further developed in the following section of this review, there is no doubt about the fact that it is critical to personalize the dose of cholecalciferol (40 IU per µg as we will see below in this review) according to baseline 25(OH)D levels and, on the other hand, concerning calcifediol, the intestinal vitamin D receptor could be exposed to supraphysiological doses that could markedly stimulate calcium and phosphorus absorption, among other differential effects of the two molecules. Moreover, it is worth mentioning that almost all the pivotal clinical trials performed to demonstrate the efficacy and safety of the majority of anti-osteoporotic drugs currently available for osteoporosis clinical treatment (whether there are bisphosphonates, PTH analogs or RANK -Receptor Activator of Nuclear factor Kappa B- ligand inhibitors) have been conducted by supplementing patients with cholecalciferol, not calcifediol, as a vitamin D form.

Efficacy and Safety Profile of Calcifediol

Vitamin D3 is the nutrient of the vitamin D endocrine system (VDES). It is derived from the steroid group that is synthesized endogenously from 7-dehydrocholesterol (provitamin D3), which is converted into 7-dehydrocholecalciferol in the upper layers of the skin by the action of ultraviolet radiation. Vitamin D is also derived from diet and may be of animal origin (D3; cholecalciferol) or vegetable origin (D2; ergocalciferol). Cholecalciferol is bound to a transport protein (vitamin D binding protein [DBP]) and reaches the liver, where it is metabolized by 25-hydroxylases (mainly microsomal CYP2R1, mitochondrial CYP27R1) to 25-hydroxycholecalciferol (calcifediol; calcidiol; 25OHD3), the prohormone and cornerstone of the VDES. In the long term, both drugs behave similarly, although calcifediol, given its pharmacokinetic properties, is preferred in situations such as liver failure, chronic kidney failure, malabsorption, and obesity. This is due to its greater solubility, decreased entrapment in adipose tissue, smaller volume of distribution, avoidance of hepatic metabolism, different mechanism of absorption. The mean half-life is different (Calcidediol, 10–22 days, cholecalciferol 14 days, calcitriol 9–10 h). In addition, it has a greater affinity for the transport protein, which enables more efficient internalization within the megalin-cubilin system.[2]

In cases of vitamin D deficiency or insufficiency, administration of fortified foods or supplements is necessary. The most widely used supplement, for which most evidence is available, is cholecalciferol, while calcifediol, i.e., 25-hydroxyvitamin D3, the main metabolite for the assessment of vitamin D status, is less used, owing to lack of availability in many countries to date. In both cases, dosage is determinant of efficacy, with higher doses or frequencies generating higher concentrations; however, other factors are also involved and interact in a different way with each drug. Calcifediol is more potent and more rapid than cholecalciferol increasing 25OHD levels, in both the short and the long term. In the long term, differences between the levels of 25OHD achieved by both molecules are reduced, although the effect of it continues being greater. In addition, the predictability of the response to calcifediol, unlike cholecalciferol, is independent of basal 25OHD levels, and its efficacy is less dependent on other comorbidities, such as obesity or malabsorption, and genetic or/and epigenetic factors.

Efficacy and Safety of 100 and 125 µg of Calcifediol Weekly Treatment

Calcifediol (25-hydroxyvitamin D3, calcidiol) has been identified as the most potent supplement for increasing 25(OH)D levels in the treatment of vitamin D deficiency. This potency is particularly clinically relevant for patients with severe deficiency, as rapid and effective repletion of vitamin D levels can be critical in improving their health outcomes. Introducing a new weekly administration formulation offers significant advantages, as it can be more convenient for many patients, providing personalized alternatives, potentially increasing adherence to the treatment and its efficacy. However, there remains a gap in our understanding of the optimal dosing regimen for weekly formulations that balances efficacy with safety, particularly in different populations, making it crucial to study new dosing strategies to refine treatment protocols and minimize potential side effects. This phase II/III, randomised, double-blind, placebo-controlled clinical trial was conducted to evaluate the efficacy of different strengths of weekly dose formulations of calcifediol. Patients were divided into two distinct cohorts based on their baseline plasma levels of 25(OH)D. In a previous publication, the efficacy and safety of weekly 75 µg and 100 µg calcifediol doses were demonstrated in patients with moderate vitamin D deficiency [10 ng/mL < 25(OH)D < 20 ng/mL].[3]

Calcifediol has consistently been shown to be an effective, predictable, and safe option for prevention and treatment of vitamin D deficiency. Overall, this trial showed that the formulations of 100 µg and 125 µg calcifediol once a week are highly effective in achieving adequate serum 25(OH)D concentrations in a rapid and safe manner. Given the comparable long-term efficacy of both weekly doses of this medicine, the weekly 100 µg calcifediol dose may represent the most appropriate treatment option for patients with severe vitamin D deficiency. Determining the appropriate dose for weekly treatment provides a new therapeutic formulation option for vitamin D deficient patients in clinical practice. Additionally, the weekly regimen has the potential to increase treatment adherence and compliance.

References

[1]Sosa Henríquez M, Gómez de Tejada Romero MJ. Cholecalciferol or Calcifediol in the Management of Vitamin D Deficiency. Nutrients. 2020 May 31;12(6):1617. doi: 10.3390/nu12061617. PMID: 32486496; PMCID: PMC7352679.

[2]Pérez-Castrillon JL, Usategui-Martín R, Pludowski P. Treatment of Vitamin D Deficiency with Calcifediol: Efficacy and Safety Profile and Predictability of Efficacy. Nutrients. 2022 May 5;14(9):1943. doi: 10.3390/nu14091943. PMID: 35565910; PMCID: PMC9102909.

[3]Pérez-Castrillón JL, Jódar-Gimeno E, Nociar J, Lojka M, Nikolov D, Cereto-Castro F, Novković S, Tarantino U, Mehsen-Cetre N, Arranz P, Martínez Ostalé C, García-Bea A, Gilaberte I. A Randomized Phase II/III Trial Evaluating the Efficacy and Safety of 100 and 125 µg of Calcifediol Weekly Treatment of Severe Vitamin D Deficiency. Nutrients. 2025 Feb 13;17(4):672. doi: 10.3390/nu17040672. PMID: 40005002; PMCID: PMC11857939.