Salvatore Minisola salvatore.minisola at uniroma1.it• Jessica Pepe1 • Pietro Donato1 • Evelina Vigna1 • Marco Occhiuto1 • Federica Ferrone1 • Federica Biamonte1 • Veronica Cecchetti1 • Vittoria Carmela Danese1 • Chiara Sonato1 • Piergianni BIondi1 • Luciano Colangelo1 • Cristiana Cipriani1
Many studies have found that the loading dose size should vary with body weight
- Children in Intensive Care need Vitamin D loading dose of 10000 IU per kg (nearing a consensus) - Oct 2016
- Quick restoration of vitamin D in children – 10,000 IU per kg loading dose was not enough – Jan 2017
- 300,000 IU loading dose of vitamin D does not help the obese much – Jan 2017
Other forms of Vitamin D, such as injection can be used for loading
- Pregnancies helped a lot by Vitamin D (injection then 50,000 IU monthly) – RCT May 2018
- Vitamin D injection of 600,000 IU (response by 10 individuals)– Sept 2017
- Vitamin D injection is far better than oral for diabetics (poor gut) – RCT March 2017
Loading period can range from 1 day to 2 months
- Restore Vitamin D levels with 200,000–400,000 IU over 2 months, followed by on-going – March 2018
- 600,000 IU of vitamin D – 42 ng at 3 months for 1 inj, 3 inj, oral monthly, oral weekly - Oct 2017
Responses to loading doses are as varied as responses to daily doses
Sometimes a loading dose is BETTER than daily dosing
- Newborn Vitamin D - single dose is better than daily – RCT Sept 2016
- Far more Vitamin D in breast milk from a 150,000 IU dose than from daily 5,000 IU – RCT May 2018
Overview Loading of vitamin D contains the following
If a person is, or is suspected to be, very vitamin D deficient a loading dose is typically given
- Loading = repletion = quick replacement (previously known as Stoss)
- Loading doses range in size from 100,000 IU to 1,000,000 IU of Vitamin D3
- The size of the loading dose is a function of body weight - see below
Unfortunately, some doctors persist in using Vitamin D2 instead of D3
- Loading may be done as quickly as a single day, to as slowly as 3 months.
It appears that spreading the loading dose over 4-20 days is a good compromise
- Loading is typically oral, but sometimes by injection (I.M,)
- The loading dose persists in the body for about 3 months
The loading dose should be followed up with continuing maintenance
Unfortunately, many doctors fail to follow-up with the maintenance dosing.
- As about 1 in 300 people have some form of mild allergic reaction to vitamin D supplements,
it appears prudent to test with a small amount of vitamin D before giving a loading dose
- The causes of a mild allergic reaction appear to be: (in order of occurance)
1) lack of magnesium - which can be easily added
2) allergy to capsule contents - oil, additives (powder does not appear to cause any reaction)
3) allergy to the tiny amount of D3 itself (allergy to wool) ( alternate: D3 made from plants )
Notes are embedded in the following text where statments are made which disagree with clinical trials
In recent years, there have been a very large number of scientific publications concerning various aspects of vitamin D, ranging from physiologic to therapeutic studies. However, despite the multiple discoveries made in this fast-growing scientific research area, numerous issues still remain unresolved [1, 2]. Examples include, though are not limited to, the definition of hypovitaminosis D (this term is used to cover cases of both insufficiency and deficiency), i.e. 20 vs 30 ng/mL; the relationship between 25(OH)D and parathyroid hormone (PTH) (linear vs non-linear and related point of inflection) [3-5]; the referent that should be considered (total vs free determination) ; and the utility of screening for hypovitaminosis vs universal supplementation .
However, one of the most heatedly debated issues is the question of what comprises appropriate treatment. Indeed, irrespective of the threshold adopted, there is uncertainty regarding the specific vitamin and the dose that should be utilised, for how long, and how to maintain the threshold once it is reached. In the following section, we will address the topic of cholecalciferol supplementation both from a theoretical and a practical point of view.
There has been much debate regarding the modalities by which vitamin D supplementation should be provided and, to discuss this issue, we propose a hypothetical situation. Let us imagine a 53-year-old woman who had her vitamin D status checked during a routine visit for bone problems after 2 years of estrogen deficiency. She reports no particular complaints apart from non-specific weakness and mild hot flushes. Her total 25(OH)D level measured by liquid chromatography tandem mass spectroscopy (a reference method) is 10 ng/mL. How can the desired value of 30 ng/mL be reached, as suggested, for example, by the Italian Society of Osteoporosis, Mineral Metabolism and Bone Diseases, as well as by National Osteoporosis Foundation, International Osteoporosis Foundation, American Association of Clinical Endocrinologists and American Geriatric Society? The target value could be achieved either via daily doses or, alternatively, she could be offered an immediate vitamin D repletion strategy.
There are several important points that should be kept in mind. First, as a rule of thumb, long-term steady-state administration of 100 IU of vitamin D raises serum 25(OH)D concentration by about 1 ng/mL (2.5 nmol/L).
No – 100 IU per ng is only true for SOME healthy persons. Most studies have found 200 IU per ng. Need even more if: overweight, poor gut, no gall bladder, already have 30 ng level of vitamin D, taking a drug which reduces Vitamin D, have poor vitamin D genes, etc
Secondly, as a pharmacological principle, it takes four half-lives for a drug to reach its steady-state level. Therefore, considering that serum 25(OH)D falls by half within 2 months, if a person is suddenly deprived of vitamin D, it should take 6 to 8 months for a full steady state of serum 25(OH)D level to be reached.
The point is that if you want to raise a patient’s serum 25(OH)D from 10 to 30 ng/mL (i.e. by 20 ng/mL) in the long term, the administration of 2,000 IU of cholecalciferol for 8 months will achieve this 30 ng/mL target in most patients. In order to sustain this level in the long term, the dose must also, of course, be maintained in the long term. However, all osteoporosis medications require, from their initiation, vitamin D sufficiency in order to be effective at achieving their full densitometric and anti-fracture effect . Moreover, there are also situations in which waiting for half a year to optimise the serum 25(OH)D serum level is not desirable. One example is the acute-phase reactions following zoledronate infusion. A number of studies have shown that vitamin D replenishment can decrease or even abolish this drug side effect . Also, in this case, a rapid conversion to a state of vitamin D sufficiency is desirable.
The pharmacological principle of a loading dose can be applied to vitamin D so that the target level of serum 25(OH)D can be reached within a few days. Again, from the point of view of basic pharmacology, a loading dose for a drug works out to be the total dose of the drug that would be given to sustain the steady-state concentrations of the drug. In the previous example, the loading dose for vitamin D works out at about 60 times the anticipated daily maintenance dose (2- month half-life = 60 days of doses, that is about 120,000 IU as a loading dose of vitamin D3). Evidently, from that loading dose onwards, the maintaining dose is required. To return to the hypothetical case, the ideal is to administer 120,000 I.U. as a bolus of vitamin D3 to raise serum 25(OH)D to its target level of 30 ng/mL, followed by 2000 IU/day from then on to maintain the appropriate levels.
From a pharmacological point of view, about a week after this dose is given as a bolus, the 25(OH)D should be at the same steady level as would be reached after 8 months of 2,000 IU per day. After this dose, the average daily dose should be kept at 2,000 or 14,000 IU once a week as an alternative regimen. In this context, it is important to note that an excess of 150,000 IU of vitamin D administration is very unusual, doses that, according to some authors, may dangerously increase falls and fractures [10, 11].
Note: Reference 10 had found that ANNUAL dosing increased falls. Other studies with monthly or more frequent dosing have not found a similar increase in falls
Cholecalciferol formulations are not available as prescription products in the USA, unlike in many European countries, where a number of formulations and doses of D3 are on the market. 50,000 IU of ergocalciferol (vitamin D2) given once a week for 8 weeks may be considered an effective strategy to target vitamin D deficiency . However, since there is no clinical trial evidence that vitamin D2 is effective , vitamin D3 is considered the most appropriate compound to prescribe to patients [14-16].
There is a long list of possible alternative strategies that have been published, the analytical examination of which is, however, not possible within this short review. A number of studies have, meanwhile, been published that seek to address the issue as to whether the same cumulative dose of cholecalciferol determines different 25(OH)D values if administered on a daily, weekly, or monthly basis. In general, the results reported in these studies are consistent with similar levels reached, independently of dosing frequencies.
There are two problems that should be briefly considered in this context. The first concerns potential toxicity. However, such doses as mentioned above are highly unlikely to cause hypercalcemia, kidney stones, and ectopic calcifications of soft tissues and vasculature, which are the most serious complications. Two patients have been reported in this Journal who suffered from primary hyperparathyroidism and who erroneously took 2,400,000 U (300,000 U/day for 8 days) and 4,500,000 U (300,000 U/day for 15 days) of cholecalciferol, respectively . Intriguingly, the unintentional over supplementation of vitamin D in these two cases caused only a moderate and temporary increase of serum and urinary calcium that were not associated with clinical signs of toxicity. These findings strongly suggest that the regulatory mechanisms of the human body are able to metabolise supraphysiological levels of vitamin D. On the other hand, the finding of frank hypercalcemia in those receiving vitamin D at the dose prescribed for supplementation and treatment could well be associated with mutations in CYP24A1. The latter polymorphisms were probably the cause of the small epidemic of infantile hypercalcemia in England in the 1950s.
The second point that should be emphasised is the well- known finding that differences are reported in the level of 25(OH)D reached among individuals following similar doses of vitamin D administration by both the oral and the intramuscular routes [16, 18, 19]. Apart from genetic considerations, these differences may be the reflection of variability in absorption, degradation, and distribution . Considering all these variables, it might be surprising that a single fixed dose is nevertheless recommended in international clinical trials. Therefore, apart from administration of the standard initial large bolus of vitamin D, prescribing according to the “one size fits all” logic cannot be justified except for practical purposes. In this context, for example, the guidelines of the American Geriatric Society report that only 51% of patients treated with the recommended dose of vitamin D (1,000 IU) achieve the goal of 30 ng/mL .
In conclusion, we believe that a “treat to target strategy” is the most desirable approach in each subject . However, in daily practice, it is difficult to apply in practical terms. There is no risk with the initial bolus administration of 100,000-150,000 IU of vitamin D: it is, in fact, needed in the great majority of cases, since severe vitamin D deficiency, defined as 25(OH)D values less than 10 ng/mL, is not common in the USA and Europe. This latter approach is sound from a pharmacological point of view and very efficiently targets the well known hypovitaminosis D pandemic round the world.
- Romagnoli E, Pepe J, Piemonte S, Cipriani C, Minisola S (2013) Management of endocrine disease: value and limitations of assessing vitamin D nutritional status and advised levels of vitamin D supplementation. Eur J Endocrinol 169:R59-R69
- Minisola S, Cipriani C, Piemonte S, Scillitani A, Pepe J (2014) Vitamin D: not all is bad. J Endocrinol Investig 37:1015-1016
- Valcour A, Blocki F, Hawkins DM, Rao SD (2012) Effects of age and serum 25-OH-vitamin D on serum parathyroid hormone levels. J Clin Endocrinol Metab 97:3989-3995
- Pepe J, Romagnoli E, Nofroni I et al (2005) Vitamin D status as the major factor determining the circulating levels of parathyroid hormone: a study in normal subjects. Osteoporos Int 16:805-812
- Souberbielle JC, Brazier F, Piketty ML, Cormier C, Minisola S, Cavalier E (2017) How the reference values for serum parathyroid hormone concentration are (or should be) established? J Endocrinol Investig 40:241-256
- Chun RF, Peercy BE, Orwoll ES, Nielson CM, Adams JS, Hewison M (2015) Vitamin D and DBP: the free hormone hypothesis revisited. J Steroid Biochem Mol Biol 148:290-297
- LeBlanc ES, Zakher B, Daeges M, Pappas M, Chou R (2015) Screening for vitamin D deficiency: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 162:109-122
- Adami S, Giannini S, Bianchi G et al (2009) Vitamin D status and response to treatment in post-menopausal osteoporosis. Osteoporos Int 20:239-244
- Bertoldo F, Pancheri S, Zenari S et al (2010) Serum 25- hydroxyvitamin D levels modulate the acute-phase response associated with the first nitrogen-containing bisphosphonate infusion. J Bone Miner Res 25:447-454
- Sanders KM, Stuart AL, Williamson EJ et al (2010) Annual high- dose oral vitamin D and falls and fractures in older women. A randomized controlled trial. JAMA 303:1815-1822
- Minisola S, Colangelo L, Cilli M, Cipriani C, Pepe J, Romagnoli E (2013) Intermittent high doses of vitamin D: a need for further studies? Calcif Tissue Int 92:487-488
- Holick MF (2017) The vitamin D deficiency pandemic: approaches for diagnosis, treatment and prevention. Rev Endocr Metab Disord 18:153-165
- Trang HM, Cole DEC, Rubin AL, Pierratos A, Siu S, Vieth R (1998) Evidence that vitamin D3 increases serum 25- hydroxyvitamin D more efficiently than does vitamin D2. Am J Clin Nutr 68:854-858
- Armas LAG, Hollis BW, Heaney RP (2004) Vitamin D2 is much less effective than vitamin D3 in humans. J Clin Endocrinol Metab 89:5387-5391
- Cipriani C, Romagnoli E, Pepe J (2013) Long-term bioavailability after a single oral or intramuscular administration of 600,000 IU of ergocalciferol or cholecalciferol: implications for treatment and prophylaxis. J Clin Endocrinol Metab 98:2709-2715
- Romagnoli E, Mascia ML, Cipriani C et al (2008) Short and longterm variations in serum calciotropic hormones after a single very large dose of ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3) in the elderly. J Clin Endocrinol Metab 93:3015-3020
- Battista C, Viti R, Minisola S et al (2013) Over-supplementation of vitamin D in two patients with primary hyperparathyroidism. Hormones (Athens) 12:598-601
- Gallagher JC, Sai A, Templin T 2nd, Smith L 2012 Dose response to vitamin D supplementation in postmenopausal women: a randomized trial. Ann Intern Med 156:425-437
- Cipriani C, Romagnoli E, Scillitani A et al (2010) Effect of a single oral dose of 600,000 IU of cholecalciferol on serum calciotropic hormones in young subjects with vitamin D deficiency: a prospective intervention study. J Clin Endocrinol Metab 95:4771-4777
- Cipriani C, Pepe J, Piemonte S, Colangelo L, Cilli M, Minisola S 2014 Vitamin D and its relationship with obesity and muscle. Int J Endocrinol 2014:841248
- American Geriatrics Society Workgroup on Vitamin D Supplementation for Older Adults (2014) Recommendations abstracted from the American Geriatrics Society Consensus Statement on vitamin D for prevention of falls and their consequences. J Am Geriatr Soc 62:147-152
- Binkley N, Lappe J, Singh RJ et al (2015) Can vitamin D metabolite measurements facilitate a “treat-to-target” paradigm to guide vitamin D supplementation? Osteoporos Int 26:1655-1660