Vitamin D Therapy in Clinical Practice: One Dose Does Not Fit All

P. J. Ryan

Disclosures

Int J Clin Pract. 2007;61(11):1894-1899. 

In This Article

Discussion

In the whole dataset, of 1028 patients with baseline measurements the mean age was age over 61.6 years, with 77.5% female. The mean vitamin D level of the whole 1028 patient group was 48 nmol/l (SD 26). For those without supplements it was 42 nmol/l (SD 22) and those on supplements, 64 nmol/l. Results for the whole dataset population have been reported in a previous study compromising most of the cohort examined and are comparable to other UK studies[24] Most patients either had a normal vitamin D or a modestly reduced value and did not have follow-up measurements.

In this present analysis subsets of patients were examined to assess the effect of therapy on vitamin D levels. A minority of 100 patients not on treatment had a low 25 hydroxy vitamin D measurement and then were started on supplements and had a second measurement. A further 210 had a vitamin D measurement, although they were already on vitamin D therapy. From both groups it is clear from the results that vitamin D therapy with conventional treatment improves serum levels of 25 hydroxy vitamin D but still leaves some patients with severe insufficiency. Additionally many more patients on conventional doses of treatment have 25 hydroxy vitamin D levels well below normal levels whether set at lower thresholds of 50 nmol/l or higher ones of around 75 nmol/l, and therefore the same dose of vitamin D does not appear appropriate for all. There therefore appears to be no substitute for measuring vitamin D levels in osteoporotic patients to ensure they are replete and when commencing treatment measurements need to be repeated to ensure they have achieved normal serum values. It is commonly suggested that 800 mg of vitamin D3 is an appropriate dose in most patients and this is supported by a recent meta analysis[25] but in real life clinical practice this study suggests that such universal guidance has to be interpreted with caution. Some may require more than 800 mg/day and some less. A significant proportion of patients on treatment will have levels of vitamin D considered to be diagnostic of vitamin D deficiency or severe insufficiency despite treatment.

The incremental increase in vitamin D levels with treatment varies widely as demonstrated in the subanalysis of those on Calcichew D3 Forte where there was a large range in the changes of vitamin D levels in response to therapy. This suggests not only do standard doses on vitamin D not always produce normal levels of vitamin D but also that there is no predictable response of vitamin D levels to standard doses of treatment. Moreover, there does not appear to be any difference in response of vitamin D levels with age with results applying both to the older and younger populations.

There are many limitations of the study that are inevitable in examining a mixed group of patients derived from clinical practice. Patients were a heterogeneous mix of individuals attending a metabolic bone clinic and taking a variety of different vitamin D supplements - some with and some without calcium. They included males and females and there was no clear assessment made of compliance with medication. We do know from various clinical trials that compliance with calcium and vitamin D is poor and this has been reported from the recent Record study,[14] Porterhouse study[13] and the Women's Health Initiative (WHI).[11] In the latter study only 76% were taking calcium and vitamin D at the end of the study and only 59% patients were taking the intended dose. In the Porthouse study only 63% were adherent at 12 months[13] and in the Record trial compliance with study medication was 65% at 2 years.[14] The low response levels in some patients in this study may inevitably therefore be a consequence of poor compliance. The study however does reflect clinical practice and compliance may be higher than in some studies as patients were under active follow-up. This was not the case for instance in the Record trial where information was obtained by questionnaire.

We also did not do an assessment of the month of the year when samples were taken. However, again the strength of the study is that it reflects clinical practice where patients are seen throughout the year. The increases in vitamin D levels found in the study suggest that there was at least some compliance with advice and prescribing. Patients and samples were spread across the whole year which should even out the effects of seasonal variation.

Many others studies as part of formal trials have shown a rise in vitamin D levels with vitamin D treatment. In the WHI calcium and vitamin D trial patients were given calcium 500 mg and vitamin D3 200 IU tablets with one taken twice a day and with meals. A cross-sectional comparison of 227 of those taking supplements with those 221 on placebo showed women on active treatment had vitamin D levels 28% higher using the Diasorin chemiluminescent immunoassay.[11] In the MORE study 6 months of treatment with vitamin D3 400-600 U and calcium 500 mg increased vitamin D levels after 6 months of treatment from 70.8 to 92.3 nmol/l in a population of 7564 women of average age 66 years.[17] The Trivedi study where patients were given 100,000 vitamin D3 by capsule every 3 months found a 40% higher vitamin D level over the placebo group after 4 years of therapy.[26] The Record study of community dwelling older men and women randomised to 1000 mg calcium, 800 IU vitamin D, a combination of both or placebo after low trauma fracture examined vitamin D3 increase in a small subset of patients and showed an increase from 35 to 60 nmol/l.[14] Our study showed an average rise in vitamin D levels of 32 nmol/l with a variety of therapies and 38 nmol/l with Calcichew D3 Forte two tablets per day in keeping with the above trials suggesting that compliance was comparable to the above studies. Some studies have shown greater rises in vitamin D levels with therapy such as a subgroup of the Chapuy French nursing home study where vitamin D levels rose from 40 to 100 nmol/l with a combination of calcium and vitamin D.[10] Other studies have shown smaller increases in vitamin D levels with treatment. For example in the US study of outpatients vitamin D levels by Margiloff et al. those on no supplements had a mean level of 25 nmol/l whereas those on 400 IU day had a level of 41 nmol/l.[7] A study of Danish community dwelling elderly showed a reduction in fractures of 16% and a rise in vitamin D levels on treatment but only a modest increase from 37 to 47 nmol/l in a small sample of 67 patients from a study of over 5000.[12]

The increases in vitamin D levels were noted in the MORE study to be greater in those with lower baseline levels, an observation also made by the Amsterdam vitamin D supplementation study.[27] In the MORE study vitamin D levels rose by 58 nmol/l when the baseline was less than 25 nmol/l but by 39 and 13.5 nmol/l when the baseline levels were 25-50 and > 50 nmol/l respectively. Our results concur with these studies with greater increases in vitamin D levels with those with a lower baseline vitamin D, 38 nmol/l where baseline levels were < 26 nmol/l but 24 nmol/l where baseline levels were > 26 nmol/l.

Concerns are expressed that higher treatment doses of vitamin D than that conventionally used may induce vitamin D toxicity, but experience with larger doses does not support these fears, and it should be noted that the upper limit considered safe to not produce adverse effects is 2000 IU/day[28] in North America and Europe and 1000 IU/day in the UK. It would be therefore reasonable to re-evaluate the current UK standard recommendations for vitamin D supplementation in view of these results and other cited studies in the paper which show that current oral supplementation practices are inadequate to achieve vitamin D sufficiency. As the benefits of high doses of vitamin D become more apparent not just for bone health but also for cancer and other chronic disease,[29,30,31,32] re-evaluation of the risk benefit analyses used to develop the broad public health recommendations for vitamin D supplementation needs to be considered. Published reports indicate that vitamin D toxicity does not occur until serum vitamin D concentrations extend above 500 nmol/l.[33]

Given compliance is an issue with vitamin D supplementation, more effort may be usefully applied to encourage persistence with treatment by perhaps face to face contact with specialist osteoporosis or practice nurses and by telephone contacts. The benefits of these approaches which have proved fruitful with other medication would however need to be tested in clinical trials. Alternative routes of vitamin D administration such as intramuscular could also be more widely utilised, especially as taking more than two calcium and vitamin D tablets per day is likely to prove onerous and produce worse compliance. Greater attention to sun light exposure should also be considered as 15-20 min of exposure to mid-day sunshine without use of UVB sun blocks can provide most adults with vitamin D equivalent to an oral dose of 250 μg per day depending on latitude and season.[29,34]

In conclusion, data from the present study suggest that there is a poor response of vitamin D levels to usual treatments in UK clinical practice which is in keeping with various clinical trials and other studies. This study establishes that inadequate vitamin D levels are achieved with what has now become usual UK prescribing. The work importantly highlights the range of responses in different individuals and shows that patients may be markedly vitamin D deficient despite being on conventional doses of therapy.


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