# Daily or intermittent vitamin D supplementation in patients with or at risk of Osteoporosis: Position statement from the GRIO

Marie-Eva Pickering, Jean-Claude Souberbielle, Anne Boutten, Véronique Breuil, Karine Briot, Roland Chapurlat, Patrice Fardellone, Rose-Marie Javier, Eugénie Koumakis, Bernard Cortet

<figure><img src="image_1.png" /></figure>

## ► To cite this version:

Marie-Eva Pickering, Jean-Claude Souberbielle, Anne Boutten, Véronique Breuil, Karine Briot, et al. Daily or intermittent vitamin D supplementation in patients with or at risk of Osteoporosis: Position statement from the GRIO. Joint Bone Spine, 2025, 92 (3), pp.105858. 10.1016/j.jbspin.2025.105858. hal-04959314

HAL Id: hal-04959314

https://u-picardie.hal.science/hal-04959314v1

Submitted on 18 Jun 2025

HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

<figure><img src="image_2.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
<figure><img src="image_3.png" /></figure>

Review

# Daily or intermittent vitamin D supplementation in patients with or at risk of osteoporosis: Position statement from the GRIO

<figure><img src="image_4.png" /></figure>

Marie-Eva Pickering<sup>a,*</sup>, Jean-Claude Souberbielle<sup>b</sup>, Anne Boutten<sup>c</sup>, Véronique Breuil<sup>d,e</sup>, Karine Briot<sup>f</sup>, Roland Chapurlat<sup>g</sup>, Patrice Fardellone<sup>h</sup>, Rose-Marie Javier<sup>i</sup>, Eugénie Koumakis<sup>j</sup>, Bernard Cortet<sup>k</sup>, in name of Groupe de Recherche et d'Information sur les Ostéoporoses (GRIO)

## INFO ARTICLE

Historique de l'article :
Accepté le 4 février 2025
Disponible sur Internet le 18 February 2025

Keywords :
Vitamin D
Osteoporosis
Fracture
Daily
Intermittent

## ABSTRACT

Advantages and disadvantages of intermittent versus daily vitamin D supplementation especially in adults with or at risk of osteoporosis are discussed by the Osteoporosis Research and Information Group (GRIO). The analysis of the literature suggests that intermittent long-term high doses vitamin D supplementation (such as 60,000 IU/month or more), may increase the risk of falls, fracture and premature death in certain populations, while daily doses of 800-1000 IU with calcium decrease falls and non-vertebral fractures in the elderly with vitamin D deficiency. In patients with or at risk of osteoporosis we hence recommend measuring the 25(OH)D concentration prior to supplementation and to provide vitamin D supplementation (with optimization of calcium intake if needed) to obtain a concentration between 30 and 60 ng/mL. We recommend the use of an initial loading dose, especially in those who need a quick repletion of vitamin D store (symptoms of osteomalacia and/or 25(OH)D concentration < 12 ng/mL, patients eligible for treatment with potent antiresorptive therapy), followed by a maintenance dose. A daily supplementation should be the rule when possible. When daily forms are however not available or not reimbursed, we recommend, like other experts, to continue using intermittent dosing with the smallest available dose (≤ 50,000 IU) and the shortest interval between doses as a stopgap until reimbursement or adequate daily pharmaceutical forms (pills or soft capsules of 1000, 2000 IU) are available.

© 2025 The Authors. Published by Elsevier Masson SAS on behalf of Société Française de Rhumatologie. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

## 1. Introduction

For the last 15 years, iterative recommendations about vitamin D supplementation in adults have been published. In 2011,

the American Institute of Medicine (IOM) first and then the Endocrine Society issued guidelines, but controversies about the recommended dietary allowance (RDAs) of vitamin D and the "normal/optimal" serum 25-hydroxyvitamin D [25(OH)D] rapidly aroused [1,2]. European countries and Australian-New Zealand societies issued also their own guidelines for the general population and for patients with or at risk of osteoporosis. In France, the Osteoporosis Research and Information Group (GRIO) issued

<footnote><sup>a</sup> Rheumatology Department, CHU Gabriel-Montpied, 63000 Clermont-Ferrand, France</footnote>

<footnote><sup>b</sup> Physiology Department, Necker-Enfants Malades Hospital, AP-HP, Paris, France</footnote>

<footnote><sup>c</sup> Biochimie Clinique, Hôpital Bichat Claude-Bernard, AP-HP, Paris, France</footnote>

<footnote><sup>d</sup> Université Côte d'Azur (UCA), Service de Rhumatologie, CHU de Nice, Hôpital Pasteur 2, 30, voie Romaine-CS 51069, 06001 Nice cedex 1, France</footnote>

<footnote><sup>e</sup> Faculté de Médecine Nice, UMR E-4320 TIRO-MATOS CEA/DRF/Institut Joliot, Université Côte d'Azur, 06107 Nice cedex 2, France</footnote>

<footnote><sup>f</sup> Rheumatology department, Cochin Hospital, 27, rue du Faubourg-Saint-Jacques, 75014 Paris, France</footnote>

<footnote><sup>g</sup> INSERM UMR 1033, université Claude-Bernard-Lyon 1, division of rheumatology, Edouard Herriot university hospital, 5, place d'Arsonval, 69003 Lyon, France</footnote>

<footnote><sup>h</sup> Rheumatology Department, University Hospital, Amiens, France</footnote>

<footnote><sup>i</sup> Rheumatology Department, Hôpital de Haute-pierre, 67000 Strasbourg, France</footnote>

<footnote><sup>j</sup> Reference Center for Rare Disorders of Calcium AND Phosphate Metabolism, Reference Center for Rare Genetic Bone Disorders, OSCAR Filière, Rheumatology Department, Cochin Hospital, AP-HP Centre-Paris university, 27, rue du Faubourg Saint-Jacques, 75014, Paris, France</footnote>

<footnote><sup>k</sup> Rheumatology Department and ULR 4490 (MabLab), University-Hospital of Lille, Lille, France</footnote>

<footnote>* Corresponding author.
Adresse e-mail : mepickering@chu-clermontferrand.fr (M.-E. Pickering).</footnote>
guidelines concerning patients with bone diseases in 2011 which were updated in 2020 [3,4]. In these updated guidelines, daily doses (1000–3000 IU) of vitamin D were suggested to have advantages over intermittent larger doses. However, considering the low level of evidence in the literature, the lack of head-to-head trials and most of all the non-availability of suitable pharmaceutical forms for daily supplementation in France, GRIO recommendations focused on a reasonable intermittent supplementation using the lowest available doses and shortest possible dosing intervals [4]. Since 2020, new vitamin D formulations have become available in France. In the light of recently published studies, this manuscript discusses the advantages and disadvantages of intermittent versus daily vitamin D supplementation especially in adults with or at risk of osteoporosis.

## 2. Vitamin D metabolism

The term "vitamin D" covers two molecules: vitamin D2 (ergocalciferol), present in vegetal food (cereals, yeasts...) and vitamin D3 (cholecalciferol) produced by the skin when exposed to ultraviolet B radiation (280-320 nm), and also present in foods of animal origin (oily fish, dairy...) [5]. Vitamins D2 and D3 can be used in preventive and curative treatment. Although diet is important, vitamin D is primarily a gift of the sun, as 90% of its body store derives from cutaneous sun exposure. Sun exposure (face, arms, hands, legs) is recommended without sunscreen for 5 to 30 minutes at least twice a week or more between the hours of 10am and 4pm [6]. The skin initiates the photochemical conversion of 7-dehydrocholesterol (7-DHC) into cutaneous previtamin D3 that is isomerized to vitamin D3. The term "vitamin D" will be used to designate both vitamins D2 and D3 since their metabolisms are similar except for a faster decline in 25-hydroxyvitamin D2 in blood after supplementation [7]. Vitamin D3 associated to the D-binding protein (DBP) in bloodstream is then activated via two hydroxylations by cytochromes in the liver and the kidney. In the liver, the activation (CYP2R1, CYP3A4, CYP27A1, CYP2J2) at position 25, leads to 25-hydroxyvitamin D3 (25(OH)D3, calcifediol) which half-life ranges from 2 to 3 weeks. A second hydroxylation (CYP27B1) in position 1 alpha, tightly regulated by PTH (stimulating) and fibroblast growth factor-23 (FGF23) (inhibiting) occurs in the proximal tubule of the kidney. This leads to 1 alpha,25-dihydroxyvitamin D3 (1,25(OH)₂D3, calcitriol, half-life 4 hours), the biologically active vitamin D3 that reaches via the blood stream target tissues where it binds to the vitamin D receptor (VDR) to exert genomic and non-genomic effects [8]. The primary function of 1,25(OH)₂D is the regulation of phospho-calcium metabolism, of normal calcium levels and bone development. The action of a 24-hydroxylase encoded by the CYP24A1 gene is now recognized as an important step in vitamin D catabolism. This enzyme, which is durably induced by elevated 1,25(OH)₂D concentrations, catalyzes the hydroxylation at positions C23 and C24 of both calcidiol and calcitriol and serves as a negative feedback mechanism to prevent hypercalcemia [9]. Vitamin D has also extra-skeletal actions, as the VDR exists in many tissues like prostate, immune cells, central nervous system, pancreas, colon, breast and parathyroid glands. Vitamin D is hence described as a steroid hormone, although it needs to be metabolized to be active and to reach its target tissues, and "vitamin" is a misnomer as it results from an endogenous body production [8].

## 3. Justification of vitamin D supplementation in patients with or at risk of osteoporosis

The concentration of circulating 25(OH)D is considered to reflect vitamin D status, with severe vitamin deficiency < 10–12 ng/mL and optimal concentrations between 20 and 50 ng/mL in the gene-

ral population. According to the GRIO recommendations, 25(OH)D concentrations should be at or above 30 ng/mL (75 nmol/L) in patients with or at risk of osteoporosis, a level that is not reached by approximately 75–80% of the general French population [4]. Reasons to support vitamin D supplementation in these patients are as follows:

* vitamin D deficiency/insufficiency often causes secondary hyperparathyroidism, especially in those with low calcium intake. Hyperparathyroidism increases bone remodeling which can lead to increased bone fragility. Vitamin D supplements are efficient to curb secondary hyperparathyroidism, with no obvious difference between daily or intermittent doses [10];

* beneficial effects of supplementation with the combination of vitamin D and calcium have been largely shown, with umbrella reviews and meta-analyses of observational and randomized trials: positive multiple health outcomes have been observed including on bone and fracture risk [11]. A recent meta-analysis (in 6 randomized clinical trials with 49,282 participants) showed a 6 and 16% reduction of any fracture and hip fracture respectively, with the association of vitamin D and calcium, five out of six included randomized controlled trials using 800 IU/day vitamin D3 [12]. It is worth noting that, as calcium was co-administered with vitamin D in these studies, the dosing schedule was daily. This meta-analysis also showed (in 11 randomized clinical trials with 34,243 participants) that neither intermittent (weekly, monthly) nor daily dosing with standard doses of vitamin D alone, without calcium, was associated with a reduced risk of fracture;

* an histomorphometry study of 675 post-mortem iliac crest biopsies identified mineralization defects in patients with a serum 25(OH)D below 30 ng/mL suggesting that vitamin D supplementation should ensure that circulating levels of 25(OH)D reach 30 ng/mL to maintain skeletal health [13];

* the role of vitamin D status in response to antiosteoporosis treatments has been discussed in the literature, and it has been shown that by correcting vitamin D levels, we optimize the effect of bisphosphonates, and by extension, probably the effect of other antiosteoporosis treatments [14]. Although vitamin D supplementation should not replace the prescription of antiosteoporosis treatments and should not be considered as an antiosteoporotic treatment on its own, an optimal vitamin D status is required for the treatment of osteoporosis.

## 4. Daily or intermittent vitamin D doses: clinical outcomes

### 4.1. Effect of supplementation on falls and fractures

Daily vitamin D plus calcium co-supplementation reduces modestly but significantly the risk of non-vertebral fracture [12]. This supplementation can only be administered daily because of the co-administration of calcium, and thus does not allow to conclude that daily supplementation with vitamin D alone (without calcium) has advantages over intermittent dosing.

#### 4.1.1. Intermittent or daily administration?

The preferable use of 1000–3000 IU daily vitamin D3 doses, particularly in older patients with falls, emerged from studies that showed either no effect or even deleterious effect of high intermittent vitamin D doses on falls and fractures while moderate daily doses decreased the incidence of falls [15–18]. It must be noted, however, that there is no comparative face-to-face studies between daily and intermittent strategies on clinical outcomes and on the risk of fracture or falls.
A large yearly dose of vitamin D3 (500,000 UI/L) increased the incidence of falls and fractures in 2256 women over 70 years old and this was confirmed in a recent meta-analysis of 15 trials that showed that intermittent or single high-dose vitamin D supplementation had no preventive effect on the risk of falls and fractures and might even increase the risk of falls [15,16]. Other studies suggest that intermittent doses may increase the fall risk (monthly 60,000 IU vitamin D3 versus placebo), or that the risk of falls is higher with higher dosages (60,000 IU vitamin D3 monthly) than with lower dosages (24,000 IU vitamin D3 monthly) [18,19]. In another meta-analysis which included 32 studies, daily administration of vitamin D was associated with a reduced risk of falls, while intermittent dose was not [17].

### 4.1.2. Daily administration and optimal dose

It is worth noting that only vitamin D supplementation with daily dose of 800 to 1000 IU was associated with lower risks of osteoporotic fracture and fall (pooled relative risk [RR], 0.87; 95% confidence interval [CI], 0.78 to 0.97 and RR, 0.91; 95% CI, 0.85 to 0.98), especially in patients with vitamin D deficiency, while doses < 800 or > 1000 IU/day were not [17]. A 12-month trial with 7 different daily oral doses of vitamin D or placebo showed that the faller rate over one year described a U-shaped curve with a maximum decrease on 1600-3200 IU doses (or serum 25(OH)D of 32-38 ng/mL [80-95nmol/L]) [10]. However, high vitamin D doses of 4000-4800 IU increased the incidence of falls in those with previous fall history [10]. In another study with 688 participants aged 70 years and older, elevated fall risk and vitamin D3 supplementation at doses of 1000 IU/day or 2000 IU/day, the risk of fall was similar compared to 200 IU/day vitamin D3; furthermore, safety concerns (first serious fall and first fall with hospitalization) with higher than 1000 IU/day vitamin D3 doses were raised [20]. In an older meta-analysis, which concluded that vitamin D reduces falls, doses lower than 700 IU/day appeared to be ineffective on fracture risk reduction [21].

### 4.2. Extraskeletal effects

Patients with or at risk of osteoporosis may often present with some other conditions related to aging or fragility that could be influenced by vitamin D supplementation. Even if it is not the primary topic of the GRIO, and thus of the present paper, we cannot ignore the results of the many intervention studies that tested the effect of vitamin D supplementation on numerous extra skeletal outcomes. As these studies have been extensively reviewed elsewhere, we only summarize the main beneficial extra-skeletal effects of daily vs intermittent vitamin D supplementation [22-24]. A multitude of RCTs have been conducted, and their results present a somewhat inconclusive picture. While some RCTs demonstrated beneficial effects of vitamin D, most did not find significant difference between vitamin D and placebo. In rare cases, vitamin D was even found to be harmful compared to a placebo. The intent-to-treat analysis of recent mega-trials which mostly included vitamin D-sufficient patients, and meta-analyses, commonly conclude that vitamin D lacks significant effects. Beneficial effects of vitamin D have been however reported in prespecified post-hoc analyses of subgroups of vitamin D-deficient subjects who received daily vitamin D supplementation but not in those who received intermittent high doses. In brief, a reduction of the risk of respiratory infections, of cancer mortality (though not incidence) and a significant decrease of blood pressure in hypertensive, but not in normotensive persons were reported [25-29]. While mortality was increased in the vitamin D group of recent mega-trials of monthly supplementation (60,000 IU/month) in patients at risk of cardiovascular disease and cancer [30,31], this finding is not universal. Additionally, daily vitamin D supplementation may mitigate the progression from a

prediabetes state to type 2 diabetes, decrease the risk of autoimmune diseases and of pregnancy pathologies like preeclampsia or gestational diabetes [32-34].

## 5. Physiological explanations for the superiority of daily over intermittent dosing on clinical outcomes

It has been shown that high intermittent intakes of vitamin D stimulate at least 2 inactivation pathways that may be considered as natural defense against an excess of vitamin D (reviewed in [35,36]). The first pathway is the 24 hydroxylation that leads to inactive metabolites (24,25(OH)₂D and 1,24,25(OH)₃D). Recent studies showed that after a large intake of vitamin D, the serum concentration of 24,25(OH)₂D will remain high longer than 25(OH)D. The intracellular synthesis of calcitriol is decreased in favor of the synthesis of 1,24,25(OH)₃D. High intake of vitamin D may thus lead to a paradoxical intracellular deficiency in calcitriol. Secondly, high doses of vitamin D may also induce a long-term increase in the secretion of FGF-23, a key regulator of phosphate and vitamin D metabolism that would diminish the synthesis of 1,25(OH)₂D. FGF 23 is also linked to an increase in all-cause mortality, in particular in case of kidney failure [37].

The liver and kidney hydroxylation are not the only pathways for the production of active vitamin D, and it has been shown that vitamin D may enter into cells that express both 25 hydroxylase and 1-alpha hydroxylase and thus be directly activated in an autocrine way. Cholecalciferol half-life is however relatively short (12-24 hours) and will thus quickly disappear from the bloodstream in case of intermittent high dose supplementation; the activation of this autocrine pathway may therefore be impaired with high intermittent rather than daily regular vitamin D intake [38].

## 6. Daily or intermittent vitamin D doses for optimal 25(OH)D blood concentration

An objective attitude to guide towards one or the other strategy is to focus on a biological parameter, the optimal serum 25(OH)D concentration as it is considered the most significant indicator for vitamin D status, and several studies have evaluated the concentrations reached with different dosages. It is however important to distinguish the situation where bolus administration and intermittent doses will be limited in time, from the daily long-term intake.

Doses of 100,000 or 200,000 IU of oral cholecalciferol every 3 months were not capable of stabilizing 25(OH)D levels in a randomized study with 60 women aged 75.0 ± 2.9 years suggesting that the interval between boluses had to be shorter [39]. A recent Bayesian network meta-analysis using Cochrane methodological quality assessment, explored in 116 randomized clinical trials, 11,376 participants, whether intermittent (weekly or monthly) vitamin D supplementation is as effective as daily supplementation in improving serum 25(OH)D levels [40]. They showed that the efficacy of intermittent vitamin D supplementation was similar to daily supplementation. Daily administration or monthly administration of vitamin D allows to reach similar levels of 25(OH)D. Daily administration is however more physiological as regards to the endogenous synthesis of vitamin D and should be preferred as it allows to reach a steady state in a more stable way.

## 7. Daily or intermittent dosing for a better adherence to vitamin D supplementation

The rationale for prescribing intermittent vitamin D supplementation is to optimize adherence to supplementation. According to
a recent consensus paper, however, there is no scientific evidence that intermittent bolus vitamin D enhance adherence compared to daily dosing, especially in high-risk osteoporosis patients [41]. In the very recent clinical guideline on vitamin D published by an expert panel of the Endocrine Society, no studies indicating better adherence to intermittent versus daily vitamin D supplementation were identified [42]. Although the authors clearly recommend daily dosing, they nonetheless, based on the preference of most osteoporosis patients for an intermittent bisphosphonate schedule, assumed that intermittent vitamin D supplementation may be more acceptable for some patients and thus improve adherence. Considering bisphosphonates as a model, to promote intermittent vitamin D has some limitation in our opinion. Indeed, bisphosphonates had to be taken after overnight fasting, and, after taking the drug, patients were required to remain upright for at least 30 min to minimize gastroesophageal reflux, and refrain from food, medications and liquids other than poorly mineralized water for at least 30-45 min to optimize absorption. Such a constraint easily explains the preference for intermittent dosing but is not transposable to vitamin D. Many patients with or at risk of osteoporosis often take daily medications for other diseases. Those who are adherent to these treatments may have no problem with daily vitamin D if acceptable pharmaceutical forms are available. Data on adhesion of patients to daily intake are however still missing.

## 8. Is there a place for calcifediol?

Two pharmaceutical preparations of calcifediol, drops for daily supplementation (5 µg/drop) and higher dose soft capsules (266 µg/capsule) for intermittent dosing, are available and reimbursed in France. By far, most of the trials that have evaluated the effects of vitamin D supplementation have focused on vitamin D3. Recent studies have shown that calcifediol, given daily, weekly, or monthly is faster and more effective than cholecalciferol in raising serum 25(OH)D levels [7,43]. Indeed, it is rapidly and better absorbed by the intestine and transported through the portal vein contrary to cholecalciferol which is transported more slowly by chylomicrons via the lymphatic system. Calcifediol is less lipophilic than cholecalciferol and is thus less sequestered in fat. Based on 9 RCTs, 1 µg calcifediol is 3.2 times more potent than 1 µg vitamin D3 in raising 25(OH)D concentration [44]. One must be cautious however as this conversion factor was found only in studies where daily vitamin D3 doses ≤ 25 µg (1000 IU) were tested. In the few studies where much higher vitamin D3 doses were used, calcifediol appeared more potent in its capacity to increase 25(OH)D level (up to 10 times). Note that there were no studies that used intermediary vitamin D3 doses (> 1000-4000 IU/day) [44]. The relationship between the dose of calcifediol and the increase in 25(OH)D concentration is linear contrary to cholecalciferol which induces a rise in 25(OH)D that is inversely related to the basal 25(OH)D level (for a given vitamin D3 dose, the lower the basal 25(OH)D concentration, the higher the increase in 25(OH)D concentration). In other words, if a given calcifediol dose rises the 25(OH)D concentration by X ng/mL in an individual, twice this dose would rise 25(OH)D concentration by (approximately) 2X ng/mL. This may be an advantage for calcifediol over cholecalciferol when the 25(OH)D concentration is measured, as knowing the 25(OH)D concentration before and after supplementation with calcifediol allows to predict with a certain degree of confidence how the 25(OH)D concentration would change if the posology is modified. This phenomenon may however become a disadvantage if the 25(OH)D concentration is not known (remember that 25(OH)D measurement is not recommended nor reimbursed in the general population in France) with a significant risk of inducing too high 25(OH)D concentration in persons who are vitamin D sufficient before supplementation. A few studies have

evaluated the effect of calcifediol given monthly during one or two years on the elevation of 25(OH)D level [45,46]. They reported that long-term administration of calcifediol maintains stable and sustained 25(OH)D concentrations, with no safety concerns. A continuous significant increase in mean 25(OH)D values from basal 20.9 ng/mL during the 2-year study was observed with the mean value at 2 years (36.7 ng/mL) not significantly different from the mean value at 1 year (41.2 ng/mL), suggesting an equilibrium was reached [46]. The maximum 25(OH)D concentration reached among the whole studied group was 79.7 ng/mL at month 24, in a patient whose basal value was 26.3 ng/mL. It must be noted that neither the concentration of 24-hydroxylated vitamin D compounds nor FGF23 levels were reported in these studies so that it is not possible to know whether monthly calcifediol or cholecalciferol present similar or different inactivating effects.

While it seems premature to recommend supplementation with calcifediol instead of cholecalciferol, especially when the 25(OH)D concentration is unknown, there are some situations where calcifediol should logically be preferred to cholecalciferol. This is the case for the situation of inhibition of hepatic 25-hydroxylase, linked to a genetic mutation in the *CYP2R1* gene or to specific long-term medications such as antiepileptics or corticosteroids. Calcifediol could also be an interesting option in conditions for which a rapid normalization of 25(OH)D levels is needed, as well as in managing vitamin D supplementation in patients with hepatic insufficiency, or in case of fat malabsorption [47]. Obesity may also be a target for calcifediol supplementation which may be less sequestered in fat mass due to its more hydrophilic nature compared to cholecalciferol. Furthermore, experimental data obtained in mice suggest that expression of *CYP2R1* is reduced in obesity and accounts in part for the decreased circulating 25(OH)D [48]. Bypassing the liver hydroxylation may be an advantage in obese patients. It could also be an interesting option in chronic kidney disease in an extended-release formulation, to help the management of secondary hyperparathyroidism in non-dialysis CKD patients [49].

It is worth noting that, contrary to cholecalciferol, very few clinical trials have tested the effects of calcifediol on clinical outcomes apart from the (nonetheless encouraging) recent open-label studies (no placebo groups) in Covid-19 patients [50].

## 9. Are there limitations to adopt a daily therapeutic strategy in vitamin D supplementation in France?

Daily rather than intermittent vitamin D supplementation has been unequivocally recommended by several independent groups of vitamin D experts, as well as in very recent international consensus statements and clinical guidelines [22,35,36,41,42,51-54]. We concur with this approach. Indeed, as indicated above, daily supplementation is more physiologic, and has been shown to exert various beneficial effects in vitamin D deficient/insufficient patients that are not found in studies where intermittent supplementation schedules have been tested. In addition, several recent trials of intermittent vitamin D supplementation (60,000 IU/month) have reported worse outcomes (increased fractures, falls, cancer mortality) in the vitamin D group than in the placebo group. Furthermore, explanations underlining clinical advantages of daily supplementation have been proposed, especially avoiding the strong stimulation of vitamin D inactivating pathways after intermittent high vitamin D doses. Even the reasons that have been hypothesized to be in favour of an intermittent supplementation (i.e. better adherence to supplementation, and quicker increase in 25(OH)D serum concentration) have not been demonstrated. In our opinion, the only reason to favour intermittent vitamin D supplementation in France is the lack of pharmaceutical forms compatible with a simple and well-accepted daily supplementation that are reimbursed by
<table><caption>**Table 1**
List of vitamin D pharmaceutical preparations available in France.</caption><tr><td>Cholecalciferol, vitamin D3</td><td>200,000 IU<br>100,000 IU<br>80,000 IU<br>50,000 IU<br>20,000 IU<br>10,000 IU<br>1000 IU<br>300 and 100 IU</td><td>Soft capsule, drinkable ampoule, ampoule for intramuscular injection<br>Soft capsule, drinkable ampoule<br>Drinkable ampoule<br>Soft capsule, drinkable ampoule<br>Soft capsule<br>Oral drops<br>Soft capsule (not reimbursed in France)<br>Drops prescribed generally to infants</td></tr><tr><td>Ergocalciferol, vitamin D2</td><td>15 “A” 600,000 IU/1,5 mL<br>15 “H” 600,000 IU/1,5 mL<br>400 IU</td><td>Drinkable ampoule<br>Ampoule for intramuscular injection<br>Oral drops provided in 2,000,000 IU/100 mL flask<br>Oral drops provided in 15 mg/100 mL flask</td></tr><tr><td>Calcifediol, 25(OH) vitamin D3</td><td>5 µg<br>266 µg</td><td>Soft capsule</td></tr><tr><td>Combinations vitamin D3 with calcium</td><td>1000 IU + 500 mg calcium</td><td>Tablets</td></tr></table>

the French Health insurance (with the exception of cholecalciferol drops (300 IU/drop) usually prescribed to babies and calcifediol drops (5 µg/drop), drops being difficult to use in older persons) (Table 1). Several unlicensed vitamin D preparations are also available in France like in other countries. The GRIO however does not recommend these preparations until evidence of the pharmaceutical quality provided by independent bodies is available. A study by Wan et al. supports this caution: the authors measured the vitamin D content of 2 pharmaceutical preparations and 11 food supplements [54]. The 11 food supplements showed a vitamin D content ranging from 41% to 165% of the labelled claim, with 8 of them failing to comply with the food supplement specification, while both the pharmaceutical forms were in accordance with the labelled claim.

In conclusion, our opinion is that, by contrast with the general population for whom a measurement of serum 25(OH)D is not a prerequisite for vitamin D supplementation, vitamin D must remain a medication in response to a need identified by 25(OH)D serum measurement in patients with or at risk of osteoporosis. In these patients (Fig. 1), we recommend measuring the 25(OH)D concentration prior to supplementation and to provide vitamin D supplementation (with optimization of calcium intake if needed) to obtain a concentration between 30 and 60 ng/mL [55]. We recommend the use of an initial loading dose, especially in those who need a quick repletion of vitamin D store (symptoms of osteomalacia and/or 25(OH)D concentration < 12 ng/mL, patients eligible for treatment with potent antiresorptive therapy), followed by a maintenance dose. As indicated above, we consider that a daily supplementation should be the rule. Due to the scarcity of available pharmaceutical forms, it is however probable that, even if informed by their physician about the superiority of daily dosage, some patients may be reluctant to take drops every day and/or to pay for their vitamin D supplementation. Thus, like several experts, we emphasize the importance of pragmatism and suggest, in these patients, to continue using intermittent dosing with the smallest available dose (not exceeding 50,000 IU, and preferably lower doses), and the shortest interval between doses as a stopgap until reimbursed pharmaceutical preparations adequate for a simple and well-accepted daily supplementation (i.e. pills or soft capsules of 1000, 2000 IU) become available and reimbursed in France [48,52,53].

## Disclosure of interest

MEP, AB, RMJ and EK declare that they have no competing interest.

JCS: Viatris, Crinex, DiaSorin, Roche Diagnostics, Amgen.

VB: Amgen, Lilly, UCB, Theramex, Besin, IBSA.

KB: ALEXION, Amgen, Besins, Kyowa Kirin.

RC: Amgen, UCB, Abbvie, Mereo, Alexion, Kyowa-Kirin, Medac, Nordic, Alfasigma, Galapagos, Novartis, Pfizer, Lilly.

<figure><img src="image_5.png" /><figcaption>**Fig. 1.** Proposition for updated modalities of vitamin D supplementation in patients with or at risk of osteoporosis, according to the pharmaceutical forms available in France, January 2025 (adapted from Souberbielle et al., 2020). *Note that 1000 IU soft capsules are not reimbursed in France.</figcaption></figure>

PF: Amgen, Arrow, Besins, Expanscience, FAES, Fresenius, Innothera, Lilly, Mylan, UCB, Theramex, X.O. Kyowa Kirin.

BC Alexion, Amgen, Aptissen, Besins, Expanscience, Lilly, Kyowa-Kirin, Novartis, Theramex, UCB, Viatris.

## Références

[1] Ross AC, Manson JE, Abrams SA, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab 2011;96:53–8.
[2] Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2011;96:1911–30.

[3] Benhamou CL, Souberbielle JC, Cortet B, et al. La vitamine D chez l'adulte: recommandations du GRIO. Presse Med 2011;40:673–82.

[4] Souberbielle JC, Cormier C, Cavalier E, et al. Supplementation in France in patients with or at risk for osteoporosis: recent data and new practices. Joint Bone Spine 2020;87:25–9.

[5] Bikle D, Christakos S. New aspects of vitamin D metabolism and action—Addressing the skin as source and target. Nat Rev Endocrinol 2020;16:234–52.

[6] Srivastava SB. Vitamin D: do we need more than sunshine? Am J Lifestyle Med 2021;15:397–401.

[7] Graeff-Armas LA, Bendik I, Kunz I, et al. Supplemental 25-Hydroxycholecalciferol is more effective than Cholecalciferol in raising Serum 25-Hydroxyvitamin D concentrations in older adults. J Nutr 2020;150:73–81.

[8] Christakos S, Dhawan P, Verstuyf A, et al. Vitamin D: metabolism, molecular mechanism of action, and pleiotropic effects. Physiol Rev 2016;96:365–408.

[9] Azer SM, Vaughan LE, Tebben PJ, et al. 24-Hydroxylase deficiency due to CYP24A1 sequence variants: comparison with other vitamin D-mediated Hypercalcemia Disorders. J Endocr Soc 2021;5:bvab119.

[10] Smith LM, Gallagher JC, Suiter C. Medium doses of daily vitamin D decrease falls and higher doses of daily vitamin D3 increase falls: a randomized clinical trial. J Steroid Biochem Mol Biol 2017;173:317–22.

[11] Chakhtoura M, Bacha DS, Gharios C, et al. Vitamin D supplementation and fractures in adults: a systematic umbrella review of meta-analyses of controlled trials. J Clin Endocrinol Metab 2022;107:882–98.

[12] Yao P, Bennett D, Mafham M, et al. Vitamin D and calcium for the prevention of fracture: a systematic review and meta-analysis. JAMA Netw Open 2019;2:e1917789.

[13] Priemel M, von Domarus C, Klatte TO, et al. Bone mineralization defects and vitamin D deficiency: histomorphometric analysis of iliac crest bone biopsies and circulating 25-hydroxyvitamin D in 675 patients. J Bone Miner Res 2010;25:305–12.

[14] Carmel AS, Shieh A, Bang H, et al. The 25(OH)D level needed to maintain a favorable bisphosphonate response is ≥33ng/ml. Osteoporos Int 2012;23:2479–87.

[15] Sanders KM, Stuart AL, Williamson EJ, et al. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA 2010;303:1815–22.

[16] Myung SK, Cho H. Effects of intermittent or single high-dose vitamin D supplementation on risk of falls and fractures: a systematic review and meta-analysis. Osteoporos Int 2023;34:1355–67.

[17] Kong SH, Jang HN, Kim JH, et al. Effect of Vitamin D supplementation on risk of fractures and falls according to dosage and interval: a meta-analysis. Endocrinol Metab (Seoul) 2022;37:344–58.

[18] Waterhouse M, Sanguineti E, Baxter C, et al. Vitamin D supplementation and risk of falling: outcomes from the randomized, placebo-controlled D-Health Trial. J Cachexia Sarcopenia Muscle 2021;12:1428–39.

[19] Bischoff-Ferrari HA, Dawson-Hughes B, Orav EJ, et al. Monthly high-dose vitamin D treatment for the prevention of functional decline: a randomized clinical trial. JAMA Intern Med 2016;176:175–83.

[20] Appel LJ, Michos ED, Mitchell CM, et al. The effects of four doses of vitamin D supplements on falls in older adults: a response-adaptive, randomized clinical trial. Ann Intern Med 2021;174:145–56.

[21] Bischoff-Ferrari HA, Willett WC, Wong JB, et al. Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials. Arch Intern Med 2009;169:551–61.

[22] Pludowski P, Grant WB, Karras SN, et al. Vitamin D supplementation: a review of the evidence arguing for a daily dose of 2000 international units (50µg) of vitamin D for adults in the general population. Nutrients 2024;16:391.

[23] Bouillon R, LeBoff MS, Neale RE. Health effects of vitamin D supplementation: lessons learned from randomized controlled trials and Mendelian randomization studies. J Bone Miner Res 2023;38:1391–403.

[24] Santos HO, Martins CEC, Forbes SC, et al. A scoping review of vitamin D for nonskeletal health: a framework for evidence-based clinical practice. Clin Ther 2023;45:e127–50.

[25] Martineau AR, Jolliffe DA, Hooper RL, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ 2017;356:i6583.

[26] Jolliffe DA, Camargo Jr CA, Sluyter JD, et al. Vitamin D supplementation to prevent acute respiratory infections: a systematic review and meta-analysis of aggregate data from randomised controlled trials. Lancet Diabetes Endocrinol 2021;9:276–92.

[27] Keum N, Giovannucci E. Vitamin D supplements and cancer incidence and mortality: a meta-analysis. Cancer 2014;111:976–80.

[28] Kuznia S, Zhu A, Akutsu T, et al. Efficacy of vitamin D(3) supplementation on cancer mortality: systematic review and individual patient data meta-analysis of randomised controlled trials. Ageing Res Rev 2023;87:101923.

[29] Chen S, Gio Gemelga G, Yeghiazarians Y. Is Vitamin D supplementation an effective treatment for hypertension? Curr Hypertens Rep 2022;24:445–53.

[30] Joseph P, Pais P, Gao P, et al. Vitamin D supplementation and adverse skeletal and non-skeletal outcomes in individuals at increased cardiovascular risk: results from the International Polycap Study (TIPS)-3 randomized controlled trial. Nutr Metab Cardiovasc Dis 2023;33:434–40.

[31] Neale RE, Baxter C, Romero BD, et al. The D-Health Trial: a randomised controlled trial of the effect of vitamin D on mortality. Lancet Diabetes Endocrinol 2022;10:120–8.

[32] Zhang Y, Tan H, Tang J, et al. Effects of vitamin D supplementation on prevention of type 2 diabetes in patients with prediabetes: a systematic review and meta-analysis. Diabetes Care 2020;43:1650–8.

[33] Hahn J, Cook NR, Alexander EK, et al. Vitamin D and marine omega 3 fatty acid supplementation and incident autoimmune disease: VITAL randomized controlled trial. BMJ 2022;376:e066452.

[34] Palacios C, Kostiuk LK, Peña-Rosas JP. Vitamin D supplementation for women during pregnancy. Cochrane Database Syst Rev 2019;7:CD008873.

[35] Griffin G, Hewison M, Hopkin J, et al. Perspective: Vitamin D supplementation prevents rickets and acute respiratory infections when given as daily maintenance but not as intermittent bolus: implications for COVID-19. Clin Med (Lond) 2021;21:e144–9.

[36] Mazess RB, Bischoff-Ferrari HA, Dawson-Hughes B. Vitamin D: Bolus Is Bogus-A narrative review. JBMR Plus 2021;5:e10567.

[37] Xue C, Yang B, Zhou C, et al. Fibroblast growth factor 23 predicts all-cause mortality in a dose-response fashion in pre-dialysis patients with chronic kidney disease. Am J Nephrol 2017;45:149–59.

[38] Hollis BW, Wagner CL. Clinical review: the role of the parent compound vitamin D with respect to metabolism and function: why clinical dose intervals can affect clinical outcomes. J Clin Endocrinol Metab 2013;98:4619–28.

[39] Välimäki VV, Löyttyniemi E, Pekkarinen T, et al. How well are the optimal serum 25OHD concentrations reached in high-dose intermittent vitamin D therapy? A placebo-controlled study on comparison between 100,000 IU and 200,000 IU of oral D3 every 3 months in elderly women. Clin Endocrinol (Oxf) 2016;84:837–44.

[40] Zhuang Y, Zhu Z, Chi P, et al. Efficacy of intermittent versus daily vitamin D supplementation on improving circulating 25(OH)D concentration: a Bayesian network meta-analysis of randomized controlled trials. Front Nutr 2023;10:1168115.

[41] Giustina A, Bilezikian JP, Adler RA, et al. Consensus statement on vitamin D status assessment and supplementation: whys, whens, and hows. Endocr Rev 2024;45:625–54 [bnae009].

[42] Demay MB, Pittas AG, Bikle DD, et al. Vitamin D for the prevention of disease: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2020;109:1907–47 [dgae290].

[43] Pérez-Castrillón JL, Dueñas-Laita A, Brandi ML, et al. Calcifediol is superior to cholecalciferol in improving vitamin D status in postmenopausal women: a randomized trial. J Bone Miner Res 2021;36:1967–78, http://dx.doi.org/10.1002/jbmr.4387.

[44] Quesada-Gomez JM, Bouillon R. Is calcifediol better than cholecalciferol for vitamin D supplementation? Osteoporos Int 2018;29:1697–711.

[45] 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;38:471–9.

[46] Occhiuto M, Pepe J, Colangelo L, et al. Effect of 2 years of monthly calcifediol administration in postmenopausal women with vitamin D insufficiency. Nutrients 2024;16:1754.

[47] Chevalley T, Brandi ML, Cashman KD, et al. Role of vitamin D supplementation in the management of musculoskeletal diseases: update from an European Society of Clinical and Economical Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) woring group. Aging Clin Exp Res 2022;34:2603–23.

[48] Roizen JD, Long C, Casella A, et al. Obesity decreases Hepatic 25-Hydroxylase activity causing low serum 25-Hydroxyvitamin D. J Bone Miner Res 2019;34:1068–73.

[49] Cozzolino M, Minghetti P, Navarra P. Extended-release calcifediol in stage 3–4 chronic kidney disease: a new therapy for the treatment of secondary hyperparathyroidism associated with hypovitaminosis D. J Nephrol 2022;35:863–73.

[50] Entrenas Castillo M, Entrenas Costa LM, Vaquero Barrios JM, et al. Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: a pilot randomized clinical study. J Steroid Biochem Mol Biol 2020;203:105751.

[51] Cavalier E, Makris K, Heijboer AC, et al. Vitamin D: analytical advances, clinical impact, and ongoing debates on health perspectives. Clin Chem 2024;70:1104–21 [hvae056].

[52] Gómez O, Campusano C, Cerdas PS, et al. Clinical practice guidelines of the Latin American Federation of Endocrinology for the use of vitamin D in the maintenance of bone health: recommendations for the Latin American context. Arch Osteoporos 2024;19:46.

[53] Pludowski P, Takacs I, Boyanov M. Clinical practice in the prevention, diagnosis and treatment of vitamin D deficiency: a central and eastern European expert consensus statement. Nutrients 2022;14:1483.

[54] Wan M, Patel A, Patel JP, et al. Quality and use of unlicensed vitamin D preparations in primary care in England: retrospective review of national prescription data and laboratory analysis. Br J Clin Pharmacol 2021;87:1338–46.

[55] Caruso G, Vescini F, Giusti A, et al. The essential role of combined calcium and vitamin D supplementation in the osteoporosis scenario in Italy: expert opinion paper. Arch Osteoporos 2024;19:99, http://dx.doi.org/10.1007/s11657-024-01451-x.