Daily oral dosing of vitamin D3 using 5000 TO 50,000 international units a day in long-term hospitalized patients: Insights from a seven year experience Show
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NOTE: ~10 months for the response to plateau Highlights
Vitamin D3 is a secosteroid hormone produced in the skin in amounts estimated up to 25,000 international units (IUs) a day by the action of UVB radiation on 7- dehydrocholesterol. Vitamin D deficiency is common due to both lack of adequate sun exposure to the skin, and because vitamin D is present in very few food sources. Deficiency is strongly linked to increased risk for a multitude of diseases, several
of which have historically been shown to improve dramatically with either adequate UVB exposure to the skin, or to oral or topical supplementation with vitamin D. These diseases include asthma, psoriasis, rheumatoid arthritis, rickets and tuberculosis. All patients in our hospital have been routinely screened on admission for vitamin D deficiency since July 2011, and offered supplementation to either correct or prevent deficiency. During this time, we have admitted over 4700 patients, the vast
majority of whom agreed to supplementation with either 5000 or 10,000 IUs/day. Due to disease concerns, a few agreed to larger amounts, ranging from 20,000 to 50,000 IUs/day. There have been no cases of vitamin D3 induced hypercalcemia or any adverse events attributable to vitamin D3 supplementation in any patient. Three patients with psoriasis showed marked clinical improvement in their skin using 20,000 to 50,000 IUs/day. Analysis of 777 recently tested patients (new and long-term) not on D3
revealed 28.7% with 25-hydroxyvitaminD3 (25OHD3) blood levels < 20 ng/ml, 64.1% < 30 ng/ml, a mean 25OHD3 level of 27.1 ng/ml, with a range from 4.9 to 74.8 ng/ml. Analysis of 418 inpatients on D3 long enough to develop 25OHD3 blood levels > 74.4 ng/ml showed a mean 25OHD3 level of 118.9 ng/ml, with a range from 74.4 to 384.8 ng/ml. The average serum calcium level in these 2 groups was 9.5 (no D3) vs 9.6 (D3), with ranges of 8.4 to 10.7 (no D3) vs 8.6 to 10.7mg/dl (D3), after excluding
patients with other causes of hypercalcemia. The average intact parathyroid hormone levels were 24.2pg/ml (D3) vs. 30.2pg/ml (no D3). Table of contents
IntroductionVitamin D was misnamed in 1922, when it was isolated from
both cod liver oil and the skin of laboratory animals subjected to UVB radiation (1). Its chemical structure was determined in the 1930s, and it was discovered to be a secosteroid hormone made by the action of UVB radiation present in sunshine on 7- dehydrocholesterol in the skin (2-3). Summit Behavioral Healthcare (SBH) is a 291-bed state psychiatric hospital in Cincinnati, Ohio.The patient
population consists of male and female adults age 18 and over. The majority of the patients have a diagnosis of severe mental illness at the time of admission, usually schizophrenia, schizoaffective disorder, or bipolar disorder. Many of the patients also have coexisting substance abuse issues. ResultsChanges in 25OHD3, calcium and iPTH blood levels over time in patients who have been on daily supplementation with either 5000 IU or 10,000 IU a day of vitamin D3 for at least 12 to 29 months.Between July 2011 and Feb 2014, a total of 36
patients were identified who received 5000 IU of vitamin D3 once daily for 12 months or longer (group 1), and 78 patients who received 5000 IU of vitamin D3 twice daily for 12 months or longer (group 2). A total of 125 and 344 serum levels of 25OHD, 225 and 515 serum calcium levels, and 26 and 61 serum iPTH levels were obtained in groups 1 and 2, respectively. Comparison of 25OHD3, calcium and iPTH blood levels in patients not on vitamin D3 (n=777) vs patients on D3 with 25OHD3 blood levels of at least 74.4 ng/ml in the past 2 years (n=418).There were no cases of
vitamin D-induced hypercalcemia or any other adverse events related to vitamin D supplementation observed in any patient. The mean 25OHD blood level in patients on D3 supplementation
was 118.9 ng/ml, vs. 27.1 ng/ml in patients not on D3 supplementation, for a difference of 91.8 ng/ml between the groups, as shown in Table 2. The distribution of serum calcium levels was very similar between the 2 groups. Changes in 25OHD3, calcium and iPTH blood levels in 3 individuals who have been taking daily doses of vitamin D ranging from 25,000 IU to 60,000 IU a day for 2 to 8 years.Three patients with psoriasis agreed to take vitamin D in doses ranging from 20,000 IU/d to 50,000 IU/d while hospitalized, and each showed marked
clinical improvement in their skin within 3 to 4 months without the development of hypercalcemia or any other adverse events related to supplementation with vitamin D. The data from 2 of these patients was discussed earlier in data set 2, and one will be reviewed in more detail in this section. Comparison of the results of 3.1 with the results from four previously discussed studiesreporting changes in 25OHD3 blood levels after daily oral supplementation with varying doses of vitamin D for 4 to 12 months, and one study reporting changes in 25OHD levels after successful use of phototherapy in treating
patients with psoriasis after 1 to 4 months. DiscussionThe possibility that oral vitamin D may be safe and effective in treating the numerous medical problems found to be strongly linked to vitamin D deficiency remains an area of great interest in medicine. A 2010 review of publications that use the term “vitamin D” in either the title or abstract revealed an
exponential increase in the publication rate of peer-reviewed papers on the topic of vitamin D over the last 40 years (3). And at the time of the writing of this manuscript, there were a total 1602 vitamin D trials registered on the Clinicaltrials.gov website (August 2018). Before
making the decision to follow this protocol in 2009, an extensive review of the literature on vitamin D dosing, toxicity, and clinical efficacy was done as discussed earlier. During this review, hypercalcemia and its attendant symptoms was identified as the main adverse reaction, but it was only associated with prolonged intake of supra-physiologic doses of vitamin D, as noted in many reports and reviews (16-17, 20, 24, 29-33, 36, 38-40, 42). We found intakes of 20,000 IU/d to 60,000 IU/d, associated with 25OHD blood levels ranging as high as 384 mg/dl, safe when taken on an extended daily basis. Many of the 25OHD blood levels we have observed are much higher than the currently defined upper limit of normal of 100 ng/ml (27, 38), yet we found no evidence of toxicity in any individual who achieved these blood levels after taking these doses for extended periods of time. There were no differences in mean serum calcium levels, the distribution of serum calcium levels, or any cases of vitamin D induced hypercalcemia in patients on vitamin D vs those not on vitamin D in any of our data sets. This is in spite of marked differences in the mean 25OHD levels (118.9 ng/ml vs 27.1 ng/ml), and in the ranges of 25OHD blood levels (74.4 to 384.8 ng/ml vs 4.9 to 74.8 ng/ml) observed. We also found that the mean and range of 25OHD levels from our patients on 10,000 IU/d for 1 to 4 months (54 ng/ml, range 14-130 ng/ml) were strikingly similar to the results observed in
patients on 10,000 IU/d for at least 4-months reported in 1977 by Stamp (median 55 ng/ml, range 40-110 ng/ml) (25), and to those obtained after 1 to 4-months of phototherapy in patients with psoriasis reported in 2010 by Ryan (median 59 ng/ml, 32-112 ng/ml) (43). It is important to note that the baseline median 25OHD level (23 ng/ml) and range of 25OHD levels (9 to 46 ng/ml) in the Ryan study were much lower than the values observed after phototherapy. This calls into question the accuracy of considering a 25OHD blood level of at least 20 ng/ml as sufficient (47-48). Other phototherapy studies in patients with psoriasis have shown similar changes in 25OHD levels before and after treatment (51). No cases of hypercalcemia were observed in any of the phototherapy reports. As discussed earlier, phototherapy has been known to be effective in treating rickets (5,13), tuberculosis (6-12) and psoriasis (14, 43, 51-53) dating back to the 1890s, 1920s, 1930s and 1940s. Phototherapy and sunshine are both currently recommended as treatments for psoriasis by the National Psoriasis Foundation (52), and phototherapy is also recommended for treating psoriasis by the American Academy of Dermatology (53). Unfortunately, we were unable to find any literature on 25OHD blood levels with extended phototherapy for disease control in patients with psoriasis. It is not currently known how high 25OHD blood levels will become with prolonged phototherapy used to maintain remission in psoriasis. This is an important void in the literature that needs to be filled, as maintenance phototherapy administered 2 to 3 times a week is required to maintain control in psoriasis (52-53). If the phototherapy is stopped, the disease will recur, unlike with TB or rickets. It would be informative to know just how high 25OHD blood levels can be with phototherapy, as it would give us more insight into what the “normal range” of 25OHD blood levels might be. Our data on extended daily dosing with 5000 IU/d and 10,000 IU/d show that the 25OHD curves don't plateau until about 12 months, which was not evident in the 5-month report from Heaney in 2003 (37). It is not clear if the same will be true with phototherapy. Interestingly, also like TB and rickets, psoriasis has also been shown to improve with oral vitamin D3. This was not only shown in the 1930s (14), but again in the 1980s, 1990s and 2000s (54-58). Topically applied vitamin D has also been known to be an effective treatment for psoriasis since the 1980s (59). In support of this hypothesis, it was shown in 2006 that the mechanism by which vitamin D is able to kill tuberculosis is by turning on a gene in the nucleus of white blood cells that makes an antibiotic called cathelicidin (60). The gene is unable to be turned on in a state of vitamin D deficiency. Once the vitamin D deficiency is corrected, the gene can be turned on and the disease cured, regardless of the method used to correct the underlying state of vitamin D deficiency (24). The decision to treat our psoriasis patients with vitamin D was made due to the multiple reports cited earlier showing its clinical efficacy and safety (14, 54-59). This includes the previous success of one of the authors (PM) in treating psoriasis using oral vitamin D3 in doses ranging up to 40,000 IU/d (57). We were also confident that the doses we used would be safe and effective due to the recent experience of two of the authors (JA, PM) in safely using comparable doses of vitamin D in treating asthma and skin cancer. The reason one of the authors (PM) made the decision to titrate the dose of vitamin D3 to see its effect on the skin cancer was due to a number of factors. This included reports from 1980 to 2006, and again in 2018, showing a strong relationship between vitamin D deficiency and increased risk for a number of cancers (61-65), others reports from the 1990s, and again in 2011, describing the ability of vitamin D to kill human tumor cells in-vitro, including melanoma and basal cell cancers (6670), reports detailing the cellular mechanisms by which vitamin D is able to arrest cancer cell growth from 2008 and 2012 (71-72), and a clinical trial from 2007 that showed a decrease risk for a number of cancers in individuals receiving daily oral vitamin D vs placebo (73). There are also now reports from 2016 (74) and 2018 (75) showing evidence of clinical efficacy of vitamin D in preventing cancer growth. One is a case report on advanced pancreatic cancer (74), in which an elderly patient, who was unable to tolerate chemotherapy, radiation, or surgery, took 50,000 IU/d of D3 for 9 months and was found to have a remarkable period of disease free progression, far beyond what would have been expected with chemotherapy. The authors were so impressed by this finding that they issued a call for more research in cancer patients with vitamin D using doses in this range. Consistent with data from the 1930's, 1940s, 1980s and 1990s discussed earlier, the three patients with psoriasis and the author with asthma all safely showed marked clinical improvement on oral vitamin D supplementation. However, they were able to do this using much lower doses of vitamin D than were used in the 1930's and 1940s. The doses these individuals used, 20,000 IU/d to 50,000 IU/d, are an order of magnitude lower than the doses of 60,000 IU/d to 300,000 IU/d used for asthma, ???? IU/d to 600,000IU/d for RA, and 100,000 IU/d to 150,000IU/d for TB. They were also within or much closer to the range of vitamin D estimated to be produced in the skin from sunshine, i.e. 10,000 IU/d to 25,000 IU/d, which likely explains why they were clinically effective, but without causing toxicity from hypercalcemia. There appears to be a dose response relationship between the clinical effectiveness of vitamin D and its toxicity. In the case of the individual with asthma, the only time he has had an exacerbation is when he dropped the dose of vitamin D3 to 5000 IU/d. His experience is also consistent with the results of a recent clinical trial in which vitamin D3 supplementation was found to be ineffective in treating patients with asthma (76). In this trial, 100,000 IU of vitamin D3 was given once, followed by 4000 IU/d of vitamin D3 given for 28 weeks, and was found to be ineffective in reducing the rate of first treatment failure or exacerbation in 201 adults with persistent asthma and vitamin D insufficiency, as compared to 207 control patients treated with placebo. The authors concluded that “These findings do not support a strategy of therapeutic vitamin D3 supplementation in patients with symptomatic asthma.” A follow-up clinical trial using vitamin D3 with higher daily doses, in the range of at least 10,000 IU/d to 25,000 IU/d, is clearly needed before this conclusion can be reached. Their results only prove that 4000 IU/d is ineffective in treating patients with asthma, not that vitamin D is ineffective in treating asthma. The 4000 IU/d vitamin D3 dose used in this asthma study is the maximum daily dose currently recommended by the Institute of Medicine (47-48, 77), but only represents 16% to 40% of the amount of vitamin D estimated to be produced from sun exposure to the skin, i.e.
10,000 IU/d to 25,000 IU/d. The patients in the asthma study were clearly deficient, with mean baseline 25OHD levels of 18.8 ng/ml. These values increased to a 25OHD mean of 42 ng/ml (range, 6.3-97.3 ng/ml) by week 12 in the treatment group, and persisted at this mean level through week 28, but remained less than 20 ng/ml in the placebo group. Similar remarkable clinical benefits using doses in this range have previously been reported in a patient with Parkinson's disease treated with 4000 IU/d of 25OHD3 (roughly equivalent to 40,000 IU/d of D3 (25)) for a year in 1997 (78), and in a pancreatic cancer patient treated with 50,000 IU/d for 9 months reported in 2016 (74). Based on these case reports, our experience, and the reports from the 1930s and 1940s discussed earlier, the failure of many clinical trials involving vitamin D3, that have been reported in the last few decades appear to be related to the use of insufficient dosing of vitamin D, which have typically ranged from 800 IU to 2000 IU/d. It is interesting to note that both Dowling (79) and Howard (17) in the 1940s observed random calcifications occur at times in patients treated with large doses of vitamin D, with both also observing that the calcifications resolved over time along with the hypercalcemia with cessation of vitamin D intake. The main treatment for vitamin D induced hypercalcemia appears to be stopping the vitamin D intake, and supportive care if necessary. Once the vitamin D levels fall, the hypercalcemia improves, calcifications will dissolve if present, symptoms abate, and patients recover uneventfully (17, 33, 79). See an expanded discussion of these references in the supplemental data section. It was with this broad background of information on dosing, safety, and toxicity, recommendations for the new UL of 10,000 IU/d, the clinical trial evidence on the effectiveness of vitamin D in treating asthma in the 1930s, psoriasis in the 1930s, 1980s and 1990s, rickets in the 1920s, RA in the 1940s, TB in the 1940s, epilepsy in 1974 and 2012 (80-81), Parkinson's disease in 1997 (78, 82), estimates of vitamin D production in the skin made in the 1970s and 1980s ranging from 10,000 IU/d to 25,000 IU/d, and the strong link between vitamin D and cancer discussed earlier, that we began to supplement hospitalized patients in 2009 with 5000 IU/d to 10,000 IU/d of vitamin D3, and have safely continued to do so through today. A few years after implementing this protocol, a national debate over vitamin D dosing, safety, clinical efficacy and toxicity erupted in 2011 with the publication of 2 contrasting sets of recommendations, one from the Food and Nutrition Board (FNB) of the Institute of Medicine (IOM) (47-48, 77), and the other from the Endocrine Society (27). This debate remains unsettled and continues today (83). In 2011, the IOM defined vitamin D deficiency as < 20 ng/ml (47-48, 77), while the Endocrine Society considered levels< 30 ng/ml to be insufficient (27). The IOM warned against achieving 25OHD levels > 50 ng/ml due to concerns for increased mortality risk, while the Endocrine Society maintained a 25OHD blood level of 100 ng/ml as the upper limit of normal. The IOM stated that a 25OHD blood level of 20 ng/ml or above was sufficient for the majority of the population, and that an intake of 600 IU/d would achieve this result in most people. They also assumed that all the vitamin D that a person gets is obtained from the diet, and recommended avoidance of sunshine due to the risk of developing skin cancer (48). However, several reports have shown that prolonged sun exposure or phototherapy results in mean and median 25OHD blood levels 2 to 3 times higher than the IOMs estimate for sufficiency (25, 41, 43, 51, 85), and can result in complete control of a disease, as has been shown for psoriasis, tuberculosis and rickets. See an expanded discussion of the issues surrounding this debate in the supplemental data section. There is also a discussion in the supplemental section
of the 25OHD blood levels obtained in 1971 when the first accurate measurements of 25OHD were made (41). They measured 25OHD blood levels in several groups of people. In a group of 8 lifeguards, mean 25OHD blood levels were 64.4 ± 8.7 ng/ml, with a range of range 53-79 ng/ml. ConclusionDaily oral intake of vitamin D3 ranging from 5000 IU/d to 60,000 IU/d for several years was well tolerated and safe in both our patients and staff. The mean 25OHD blood levels in our patients appear to take around 12 months to plateau on 5000 IU/d and 10,000 IU/d. References
What happens if you take 10000 IU of vitamin d3 daily?NEW YORK (Reuters Health) - Vitamin D supplementation in doses up to 10,000 IU/day appears to be safe and well tolerated, though higher doses increase the risk of hypercalciuria and mild hypercalcemia, according to a secondary analysis from the Calgary Vitamin D randomized controlled trial.
Is 10000 units of vitamin d3 too much?Up to 4,000 IU per day is generally considered the safe upper limit, however, doses up to 10,000 IU/day have not been shown to cause toxicity. In fact, many cases of vitamin D toxicity have been a result of dosing errors leading to significantly higher amounts being ingested.
What is the maximum amount of vitamin d3 you can take per day?Unless your doctor recommends it, avoid taking more than 4,000 IU per day, which is considered the safe upper limit. Choose food over pills.
How much vitamin d3 IU is too much?Taking 60,000 international units (IU) a day of vitamin D for several months has been shown to cause toxicity. This level is many times higher than the U.S. Recommended Dietary Allowance (RDA) for most adults of 600 IU of vitamin D a day.
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