Vitamin D loading dose of 30,000 IU twice a week is safe and effective – RCT July 2023

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Controlled randomized open label clinical study comparing the safety and efficacy of loading schedules in vitamin D deficient patients

The J/ of Steroid Biochemistry and Molecular Biology Vol 231, July 2023, https://doi.org/10.1016/j.jsbmb.2023.106330
Istvan Takacs a, Bence Bakos a, Zsuzsanna Nemeth a, Bela E. Toth b, Balazs Szili a, Peter Lakatos a

Rapidly restoring vitamin D levels to normal might be desirable in certain clinical situations. Larger doses of supplementation, have been shown to increase bone loss and the risk of falls. The optimal way to perform vitamin D loading safely and effectively is still not well elucidated. Our study was aimed to assess the safety and efficacy of two oral vitamin D loading protocols. Sixty-nine subjects with vitamin D deficiency (25OH-vitamin D OH)D) < 20 ng/ml) were included. Thirty-five participants received 30 000 IU of vitamin D3 per week for 10 weeks (group Slower Loading Dose (SLD and thirty-four received 30 000 IU twice weekly for 5 weeks (group Moderate Loading Dose (MLD)) resulting in a loading dose of 300 000 IU for all subjects. Following this initial loading phase, both groups received 30 000 IU biweekly for 4 weeks to test whether the recommended daily vitamin D supplementation in range of 2000 IU dose-equivalent could maintain the achieved levels. Seventy-nine percent of those subjects treated in group SLD and everyone in group MLD achieved a 25(OH)D level of 30 ng/ml, which is the lower limit of the recommended normal range in Hungary. The mean increase in 25(OH)D was significantly higher in group MLD than in group SLD (38.6 ± 1.80 ng/ml vs 46,6 ± 1.80 ng/ml). No significant decrease was observed with the administration of the maintenance dose. There were no clinically significant changes in serum or urine calcium, and bone biomarkers in either group. Both protocols were found to be safe and effective, but the five-week dosing caused a significantly greater increase in 25(OH)D. A maintenance dose applied for four weeks after the loading protocol did not raise 25(OH)D levels further but maintained the achieved increase. The administration of 30 000 IU of vitamin D3 twice weekly for five weeks is a rapid, effective and safe way to treat vitamin D deficiency in vitamin D deficient patients.

Introduction
Given its prevalence and association with numerous skeletal and extraskeletal health outcomes, vitamin D deficiency is considered a major global public health issue [1]. Decreased sunlight exposure due to low ambient UV-B radiation or clothing habits and sunscreen use, as well as several medical comorbidities increased the risk of vitamin D deficiency. In a representative survey using a standardized measurement method, 24% of the US population and 40.4% of the European population had 25(OH)D values below 20 ng/ml [2], [3].

Despite its importance, there is no consensus in the world today on the dose and optimal method of vitamin D supplementation in vitamin D deficiency. Recommended daily doses vary widely between 400 and 2000 IUs. Part of the reason for this incongruity is that different organizations have disparate recommendations regarding vitamin D sufficiency [4], [5]. The use of 20 ng/ml as the lower limit of normal serum 25(OH)D might be supported be the significant rise in clinical and laboratory abnormalities below this value. However, a number of observational and interventional studies have confirmed that increased parathyroid hormone (PTH) levels and osteomalacia-like bone lesions already appear below 30 ng/ml PTH [6]. 25(OH)D concentrations above this threshold also seem to be beneficial for non-skeletal health. The incidence of mortality, autoimmune diseases, certain infections and tumor types all seem to increase below this limit. Therefore, many societies now consider a 25(OH)D value of 30 ng/ml as the lower end of the normal range [7], [8]. In order to maintain levels around this value, an oral daily intake of approximately 1000–2000 IUs of vitamin D3 is required during periods of prolonged UV-B deprivation, which is commonly due to geographic or individual environmental factors [5], [9]. In case of established deficiency, however, adequate serum levels can only be restored over a period of several months with this daily dosing [10]. Furthermore, several RCTs have verified that daily dosing is associated with poor adherence [11], [12].

The rapid replenishment of stores and the ease of administration are two of the most important factors why single high-dose vitamin D supplementation has been experimented with for decades. Annual and semi-annual administration have been associated with a number of side effects possibly due to the non-physiological fluctuations in levels of vitamin D metabolites. Administration of single high dose has been associated with a transient surplus of calcitriol and sclerostin, but has shown an inability to maintain ideal vitamin D levels in the long term [13]. This potentially leads to increased fall risk and bone fragility [14]. Thus the single bolus administration of hundreds of thousands international units (>300 000 IU) of vitamin D has been eliminated from daily practice. On the other hand, the most commonly used daily dosing regimens raise serum levels slowly over the span of several months making them inadequate in clinical situations where faster correction is required. Although rapid correction of vitamin D deficiency is usually not required, under such circumstances a safe and effective loading dose is indicated. Considering the degree of vitamin D deficiency, vitamin D supplementation is usually administered daily or weekly until the serum 25(OH)D level normalizes, which generally takes some weeks [15], [16]. Medical conditions requiring urgent correction of vitamin D deficiency include osteoporotic hip fracture where recovery is improved and the risk of falling is reduced with the normalization of vitamin D status [17], [18]. The COVID-19 pandemic has also drawn attention to the importance of rapid and safe supplementation. In SARS-CoV-2 virus infected patients vitamin D deficiency is associated with more severe disease and a higher risk of mortality [19], [20]. Randomized trials have also shown a survival benefit in COVID-19 infection with vitamin D supplementation which quickly became part of the protocol for the management of the disease in many countries [21].

The biological half-life of 25(OH)D is approximately 3 weeks. This, in combination with the storage of vitamin D in adipose tissue enables for weekly or monthly dosing that rapidly replenishes stores meanwhile avoiding side effects that occur with larger single doses [22].

In this study we have investigated the safety and efficacy of two types of loading dose regimens. In slower dosing schedule (SLD) weekly and in moderate dosing schedule (MLD) twice weekly 30 000 IU vitamin D3 were given for ten and five weeks respectively. Following this loading phase, we have also assessed the efficacy of bi-weekly 30 000 IUs in maintaining sufficiency.

Section snippets
Study criteria and participants
Subjects aged between 18 and 70 years, drawn from seven Hungarian study centers, were recruited between August 2018 and May 2019. The subjects’ 25(OH)D levels were less than 20 ng/ml and all premenopausal women were using oral contraceptive regimens.. . .

Exclusion criteria were as follows: significant obesity (BMI > 36); increased serum calcium level (se Ca>2.60 mmol/L); verified or suspected hypercalcemia in the last year; persistent hypercalciuria or symptoms of kidney stone in the last year; . . .

Results
Sixty-nine subjects with vitamin D deficiency (25OH-vitamin D (25(OH)D) < 20 ng/ml) were included for the analysis. Baseline characteristics of the patients by group are shown in Table 2. ..

For the initial, loading dose phase the main effect of loading on vitamin D levels was highly significant (p < 0.001, r = 0.93). The mean increase in 25(OH)D levels was 27.84 ± 1.4 ng/ml for all participants. The main effect of group (p = 0.004, r = 0.34) and the group x loading (p = 0.017, r = 0.29)

Discussion
Our randomized controlled trial is the first to demonstrate that oral vitamin D3 tablets of 30 000 IUs per week for 10 weeks and 30 000 IUs twice weekly for five weeks are both effective and safe forms of supplementation for the treatment of vitamin D deficiency. Even though the cumulative dose of vitamin D3 was identical, the shorter loading protocol resulted in a faster correction of vitamin D deficiency and a more prominent increase in 25(OH)D levels. The Institute of Medicine (IOM) and the . . .

36 references

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Vitamin D Life – Loading Dose of Vitamin D category contains:

200 items in category
see also Overview Loading of vitamin D   Overview Toxicity of vitamin D
Better than Daily 1: Fewer chances to forget, 2) Gets past receptor barrier
Injection category has 62 items
 
It appears that over 1 million Vitamin D loading doses have been taken
Doses ranged from 100,000 to 600,000 IU over a period of a day to a month
No reports of serious adverse reactions
Many studies report on the benefits resulting from loading doses

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