We investigated which formulation and dosage frequency of oral vitamin D are best to promote high adherence in adult outpatients in need of a cholecalciferol substitution. We followed Swiss regulation on treatment recommendations and administered equivalents of 800 IU daily in liquid form (weekly oily drops of 5’600 IU or monthly alcoholic solution of 24’000 IU) and solid from (weekly tablet of 5’600 IU or monthly capsule of 20’000 IU). A higher adherence was observed with monthly administration, independently of the formulation. However, after six months of intake, a solid dosage form such as tablets or capsules was preferred together with monthly frequency. Thus, monthly administration of solid forms seems most suitable. Remarkably these results correspond to the conclusions of the focus group’s discussion prior to study initiation. After three and six months of intake, all serum values of vitamin D had increased. However, optimal serum values were reached with solid substitution only by half of the participants and with liquid substitution by even only 26% of them. Potential reasons for this difference may be related to inaccurate dosing using the pipette, or a larger proportion of participants under solid forms who terminated the study in spring time. An influence of sun radiation cannot be excluded. On the other hand, the strength of the capsules was lower than intended. Therefore, differences in serum values between the two formulations need careful interpretation.
Some exceptions to a monthly administration of a solid form may exist for specific groups of patients. For example, patients with a multicompartment adherence aid may prefer a daily or a weekly administration. For infants who are not able to swallow capsules or tablets, liquid dosage form as non-alcoholic product may be preferable. Weekly or daily dosing seems easiest to manage for parents.
Vitamin D values increased in all treatment groups; however, 82% and 63% of the patients 63% x did not reach an optimal value > 75 nmol/l after three and six months of intake, respectively. Our data clearly show that the administration of 800 cholecalciferol IU/day given as cumulative dose is not sufficient to treat profound vitamin D deficiency. These findings are in line with an earlier trial conducted with a similar number of participants [24]. A dosing scheme that reliably leads to sufficient (> 50 nmol/l) or optimal (> 75 nmol/l) vitamin D serum values without exceeding the maximum dosage of 4.000 IU vitamin D per day as indicated by the Institute of Medicine [9] would be desirable.
The advantage of a dosing pipette was not evident to most study participants. The task of measuring the correct dose was not successfully achieved in 28% of patients, despite individual instructions from the investigating doctors. To avoid this kind of error, liquid solution could be manufactured to deliver an entire dose such as a drink ampule in analogy to a capsule or a tablet.
We considered the tolerance of 24 hours for weekly intake which corresponds to a grace period of 15% appropriate for an adherence study. However, the acceptance limit for timing adherence with a range of 15% is discriminatory compared to more common 25% [25]. For actual implementation outside an adherence trial, the intake interval of vitamin D is far less critical.
Our study has several strengths. First, instead of retrospective patient surveys, we used electronic devices to assess adherence. Thus, we obtained objective adherence values that are comparable over the different dosage frequencies without recall bias, which represents the main drawback of adherence questionnaires. Second, only patients with vitamin D deficiency of < 50 nmol/l were included in our study. Third, four preparations were compared which were commercially available in Switzerland or Germany. Thus, our results can be generalised and used to develop further formulations.
The study also shows some limitations. First, adherence values can be expected to be higher in volunteers who have been informed in detail of treatment objectives and are aware of monitoring procedure. Thus, the higher adherence measurement in the first treatment period could result from this Hawthorne effect. Second, the recommendation of 800 IU cholecalciferol daily corresponds to the cumulative dose of 24.000 IU per month [9]. No such solid product was commercially available in Switzerland nor in the surrounding countries (France, Germany, Italy, Austria). Thus, we used the closest dosage as possible which is 20.000 IU in form of capsules. Consequently, we can assume that the measured effect of monthly vitamin D capsules would have been even more pronounced with 24.000 IU cholecalciferol. Third, we terminated the study after the recruitment of 106 instead of 128 participants end of April. This decision was made to avoid the influence of sunlight on individual serum vitamin D values. We preferred having a smaller sample size than biased laboratory findings.