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UK/FLY/2023/2636 v3| November 2023


The ABC of Vitamin D

Now available on demand - This event outlines the role of vitamin D within the human body, along with the effects of vitamin D deficiency on health. It explores the evidence base for the pharmacological management of vitamin D deficiency and examines the clinical benefits of different treatment options for hypovitaminosis D.

Colecalciferol vs Calcifediol

Hypovitaminosis D is a common problem worldwide including in the UK.1, 3 Until recently, the most common form of vitamin D dietary treatment was vitamin D3 (colecalciferol).2 Calcifediol (25(OH)D3), a precursor of the biologically active form of vitamin D comprises an alternative treatment strategy to enhance vitamin D blood levels. Calcifediol, unlike colecalciferol, carries a hydroxyl group which makes it more hydrophilic than colecalciferol.2

Figure 1. The molecular differences between calcifediol and colecalciferol.

This molecular alteration underscores significant advantages compared to colecalciferol, as outlined below.

1. Domnisol®(calcifediol monohydrate) offers superior intestinal absorption versus colecalciferol. The intestinal absorption of colecalciferol depends on the presence of bile acids.3 In patients with fat malabsorptive states, the intestinal absorption of colecalciferol may be compromised, whereas Domnisol is absorbed and transported directly into the boodstream via the portal vein. Thus, the absorption of calcifediol is largely preserved3 and is not affected in patients with fat malabsorption deficiencies.4

Domnisol is one step closer in the vitamin D metabolic pathway.

2. Domnisol (calcifediol monohydrate) avoids the requirement for the first (hepatic) hydroxylation step required before colecalciferol can become biologically active vitamin D (1,25-dihydroxyvitamin D). Domnisol is independent of hepatic hydroxylation and efficacy of treatment remains unaffected by liver diseases and other conditions that may affect liver function.4
3. Domnisol (calcifediol monohydrate) has a predictable and linear dose-response curve irrespective of baseline serum vitamin D levels. With calcifediol, the relationship between dosage and final vitamin D concentrations in the blood is linear. Increasing the dose respectively increases the vitamin D concentrations in the blood. On the contrary, with colecalciferol, increasing the daily dose of colecalciferol treatment does not result in a linear increase in vitamin D serum levels. The higher the basal vitamin D levels, the smaller the observed increase during treatment.3,4

Figure 3. Calcifediol and colecalciferol dose response curves. Mean changes ("delta") in serum 25(OH)D concentration after oral treatment with colecalciferol (A) or with calcifediol (B) according to baseline serum 25(OH)D concentration, as reported in RCTs comparing both oral treatment options.6

4. Domnisol (calcifediol monohydrate) achieves target serum vitamin D concentrations more rapidly than colecalciferol. Domnisol was found to be significantly more efficient and more rapid in shifting healthy post-menopausal women into a desirable vitamin D serum level compared to colecalciferol.1,2,3 The rapid increase in vitamin D blood levels may be beneficial in clinical situations where the rapid increase in vitamin D status is required. Examples of this are in patients with symptoms due to vitamin D deficiency or before initiation of antiresorptive treatment or anabolic bone therapy in patients at risk of fracture.3
5. Domnisol (calcifediol monohydrate) compared to colecalciferol, has an additional hydroxyl group. The additional hydroxyl group allows Domnisol to become more hydrophilic than colecalciferol and consequently is less prone to accumulation in adipose tissue. This difference also results in a shorter elimination half-life for Domnisol compared to colecalciferol. Domnisol’s shorter half-life provides an advantage over colecalciferol for management of intoxication such as hypercalcemia or hypercalciuria.3,5

6. Domnisol’s pharmacokinetic properties underpin a different frequency of administration in routine maintenance therapy of 1 capsule/month.6

Studies have shown a poor adherence with once-daily oral vitamin D treatments, with compliance rates ranging from 20–60%.7-9 A randomised crossover study in 97 adults assessed adherence and patient preferences to different vitamin D formulations (capsule, tablets, or liquid form) and dosing frequencies (weekly vs. monthly). Understanding what steps can be taken to improve adherence to vitamin D supplements may be important to improve their efficacy. The study suggests that patients prefer the monthly vitamin D option, and this dosing frequency may lead to greater adherence compared with weekly or daily dosing.10

1. Manuel Sosa Henriquez, et al. 2020.Colecalciferol or calcifediol in the management of vitamin D deficiency. Nutrients,12 1617
2. Heike Annette Bischoff-Ferrari, et al.2012. Oral Supplementation with 25(OH)D3 versus vitamin D3: Effects on 25(OH)D levels, lower extremity function, blood pressure and markers of innate immunity. Journal of Bone and Mineral research. Vol. 27, No 1, 160-169
3. Esteban Jodar, et al.2023. Calcifediol: a review of its pharmacological characteristics and clinical use in correcting vitamin D deficiency. European Journal of Nutrition.
4. J.M. Quesada-Gomez, R. Bouillon. 2018. Is Calcifediol better than cholecalciferol for vitamin D supplementation? Osteoporosis International 29, 1697-1711
5. Cianferotti Luisella, et al. 2015. The clinical use of vitamin D metabolites and their potential developments: a position statement from the European society for clinical and economic aspects of osteoporosis and osteoarthritis and the international osteoporosis foundation. Endocrine. 50 (1) 12-26
6. Domnisol SmPC
7. Conti F et al.2012. Adherence to calcium and vitamin D supplementations: results from the ADVICE survey. Clin Cases Miner Bone Metab.;9(3):157–160.
8. Segal E et al.2009. Low patient compliance- A major negative factor in achieving vitamin D adequacy in elderly hip fracture patients supplemented with 800IU of vitamin D3 daily. Arch Gerontol Geriatr.;49(3):364–367.
9. Jackson RD, et al.2006. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med.;354(7):669–683.
10. Rothen JP et al.2020. Oral intermittent vitamin D substitution: influence of pharmaceutical form and dosage frequency on medication adherence: a randomized clinical trial. BMC Pharmacol Toxicol.;21(1):51.
11. Pérez-Castrillón JL, Dueñas-Laita A, Gómez-Alonso C, et al. Long-Term Treatment and Effect of Discontinuation of Calcifediol in Postmenopausal Women with Vitamin D Deficiency: A Randomized Trial. J Bone Miner Res. 2023;38(4):471-479.