Introduction
Vitamin D has been shown to have immunomodulatory benefits besides being beneficial for musculoskeletal and cardiovascular health.(Reference Nair and Maseeh1) Administering cholecalciferol or ergocalciferol, the prevalent formulations of vitamin D, manifests a heterogeneous response across individuals in terms of raising 25-hydroxyvitamin D [25(OH)D] concentrations. The elevation in [25(OH)D] concentrations resulting from supplementation is contingent upon factors such as the individual’s age, baseline 25(OH)D concentrations, and body mass index.(Reference Tobias, Luttmann-Gibson and Mora2–Reference Shab-Bidar, Bours and Geusens4) Calcitriol, the metabolically active 1,25-dihydroxy vitamin D, has been used in specific patient populations with impaired metabolism and vitamin D activation, such as individuals with chronic kidney disease and hypoparathyroidism. Nevertheless, its use is associated with a markedly elevated risk of hypercalcaemia and hypercalciuria.(Reference O’Donnell, Moher and Thomas5)
Calcifediol, the 25-hydroxylated form of vitamin D, is used sparingly compared to the previously described forms despite significant advantages over cholecalciferol. Calcifediol is absorbed with much higher efficacy than cholecalciferol, with studies showing a mean absorption efficacy of 85.8% with cholecalciferol and 93.3% with calcifediol in healthy controls.(Reference Bouillon and Gomez6) Calcifediol is also absorbed equally well in subjects with coeliac disease or any other cause of intestinal malabsorption compared to those without malabsorption. This is because the absorption of calcifediol is not dependent on micelle formation.(Reference Bouillon and Gomez6) The liver-independent action of calcifediol also makes it the preferred formulation for individuals with advanced liver cirrhosis.(Reference Jodar, Campusano and de Jongh7) Calcifediol has been shown to be 2.5 to 5 times more potent than cholecalciferol and has a linear dose-response relationship independent of baseline 25(OH)D concentrations.(Reference Quesada-Gomez and Bouillon8) Moreover, calcifediol is safer than calcitriol, with a much lesser incidence of hypercalcaemia and hypercalciuria than the latter.(Reference Vaes, Tieland and Regt9–Reference Jetter, Egli and Dawson-Hughes15)
Our previous study demonstrated the efficacy and dose-dependence effects of oral calcifediol supplementation on circulating 25(OH)D concentrations in young adults with vitamin D deficiency, with comparable levels of ALP, PTH, and 1,25(OH)2D between the low dose (25 µg) and high dose (50 µg) groups.(Reference Vaes, Tieland and Regt9–Reference Minisola, Cianferotti and Biondi17) Since it was an 8-week interventional study, the long-term impact of calcifediol supplementation was not known. There is also limited literature on the comparative efficacy of calcifediol with cholecalciferol when used in equivalent doses. Previous studies from Jetter et al. and Bischoff-Ferrari et al. have compared 20 µg calcifediol with 20 µg cholecalciferol while study from Shieh et al. has compared 60 µg of cholecalciferol with 20 µg of calcifediol.(Reference Vaes, Tieland and Regt9–Reference Wittwer21)
The present study was designed to evaluate the efficacy and safety of calcifediol 25 µg in raising serum 25(OH)D levels compared to cholecalciferol sachet 100 µg (4000 IU) in healthy individuals with long-term supplementation after 6 months of follow up. The doses of 25 µg of calcifediol and 100 µg of cholecalciferol were chosen because 100 µg (4000 IU) of cholecalciferol is the maximum tolerable dose as recommended by the National Academy of Medicine, and available literature suggests a 2.5–5 times higher potency for calcifediol vis-à-vis cholecalciferol.(Reference Quesada-Gomez and Bouillon8–Reference Navarro-Valverde, Sosa-Henriquez and Alhambra-Exposito19) Thus, considering potency of calcifediol to be 4 times higher than cholecalciferol, a dose of 25 µg of calcifediol was chosen. Moreover, efficacy and safety of 25 µg of calcifediol was known from the earlier study.
Material and methods
The study aimed to evaluate the rise in serum concentration of 25(OH)D with daily calcifediol capsules versus daily cholecalciferol sachets in healthy subjects. It was conducted by the Department of Endocrinology, PGIMER Chandigarh (latitude 30.7° N, 76.8° E), by recruiting individual healthy volunteers aged 18–50 years with vitamin D deficiency [25(OH)D < 75 nmol/L] at baseline and who provided consent (the hospital staff and allied school). Individuals with serum 25(OH)D levels exceeding 75 nmol/L, already taking vitamin D supplementation, chronic organ dysfunction or gross co-morbidities like chronic kidney or liver disease, primary hyperparathyroidism, known malabsorption syndrome, afflicted with Human Immunodeficiency virus (HIV) or other known immunodeficiencies, active malignancy, psychiatric illness, pregnant, or lactating women, having hypercalcaemia (>10.2 mg/dl), hypercalciuria (spot urine calcium creatinine ratio more than 0.2/mg/mg or 4 mg/kg/g), renal stone disease or nephrocalcinosis at baseline, were excluded. Those on any form of chronic glucocorticoid therapy (>5 mg/day in the prior three months) or other immunosuppressive treatments were also excluded. The Institutional Ethics Committee of PGIMER approved the study (IEC-03/2023-2687). This study was performed in accordance with the Helsinki protocol.
The study design was an open-label, interventional study, with six-month intervention and follow-up. Convenience sampling was used. We calculated the retrospective power of the study due to unequal sizes and high SD of serum levels at six months. We hypothesised that daily calcifediol capsules and daily cholecalciferol sachet administration would accomplish a similar serum concentration of 25(OH)D in healthy subjects. Power calculation was performed using an equivalence test of means and two one-sided unequal-variance t-tests. The sample sizes were 62 in the calcifediol group and 41 in the cholecalciferol group leading to an allocation ratio of 1.5:1. The study achieved 77% power at a 5% significance level when the equivalence limits are −25 and 25, the actual difference between the means is 5, and the standard deviations are 48 and 34 in the two groups, respectively (PASS 2021, v21.0.6).
Calcifediol capsules were generously provided by Dishman Carbogen Amcis Ltd. Cholecalciferol sachets for the study were manufactured by Thar Pharmaceuticals Ltd. (Ahmedabad, India). The allied school staff were assigned to the calcifediol capsule group (25 µg), and the hospital staff received a daily cholecalciferol sachet (100 µg = 4000 IU) for six months. This study was conducted from the month of January to July. Jan-Mar is winter months and Apr-July is summer months in Chandigarh. During winter months all the subjects were exposed to sunlight roughly for 15–30 min per day with 5–7% of body surface area (face & head) and during the summer season 15–17% of body surface area are exposed to sunlight. In city of Chandigarh where the study was conducted, dermal vit. D synthesis is possible from second half of February to end of November. The ultraviolet ray B1 exposure during summer and sunny monsoon month (less pollutants in the atmosphere) lead to increase in 25(OH) vit.D levels of 7-12 nmol/L with daily exposure of 15–20% of body surface area for at least 30–45 minutes at the end of 4 weeks. However, mid-day ultraviolet B ray (11:00–13:00 can be sufficient for much of the year as the pollutants and suspended particles remains same in all the 3 seasons except in winter where it is very high following monsoon rains it is the lowest. The winter(December - mid February) gains are typically minimal.(Reference Marwaha, Yenamandra and Sreenivas3) There is caveat that, in real-world settings, responses vary by skin phenotype, baseline status of Vit.D cloud/air pollution, time of day, body surface area exposed, and habitual sun exposure behaviours.
The baseline clinical information of participants included demographic factors, anthropometric measurements, and biochemical analyses. Body composition was also assessed using the BC-601 (Tanita Corporation, Tokyo, Japan), a foot-to-foot bioimpedance analysis device. Patients also underwent an abdominal ultrasound before screening and at the end of the study to look for renal stones and nephrocalcinosis. Initial assessment included serum calcium (Ca), phosphorus (PO4), albumin (Alb), alkaline phosphatase (ALP), urine calcium creatinine clearance ratio (CCCR), and hormonal markers such as serum 25(OH)D, intact parathyroid hormone (iPTH), 1,25(OH)2D and beta C-terminal cross-linked telopeptide of type I collagen (βCTX), and Procollagen 1 Intact N-Terminal Propeptide (P1NP). Serum Ca, PO4, Alb, and ALP were determined using the COBAS 8000 Analyzer (ECLIA, Roche Diagnostics, Germany). Albumin-corrected calcium was utilised for analysis. Serum 25(OH)D and iPTH were quantified through electrochemiluminescence assay (ECLIA, COBAS 8000, Roche Diagnostics, Germany) with a coefficient of variation of 6–8%. 1,25(OH)2D was measured using a chemiluminescence assay (CLIA, Diasorin Liasion) with a reference range of 47.7–190.3 pmol/L, limit of detection of 1.7 pmol/L, and a measuring range of 12-480 pmol/L. The CCCR was assessed using a fully automated photometric biochemical analyser (Photometric, Em 200, Transasia). Biochemical parameters were reassessed after three and six months.
The team consistently reinforced daily supplementation through telephone conversations or messaging. Compliance was evaluated by counting capsules and sachets during each follow-up visit, and any adverse events were documented at these sessions. Missing more than 20% doses over a six-month period was considered as non-compliance.
Statistical analysis was conducted with the IBM Statistical Package for Social Sciences (SPSS) version 29. The Kolmogorov–Smirnov test was used to assess the normality of data. Normally distributed continuous variables were expressed as mean ± standard deviation (SD) and were compared using a t-test or analysis of variance (ANOVA) with multiple pairwise comparisons. Continuous variables that did not follow a normal distribution were represented as median (interquartile range), and comparisons were carried out using the Wilcoxon signed-rank test. The current study’s baseline differences were significant for serum 25(OH)D, iPTH, and body fat percentage. Therefore, we conducted a repeated measures ANCOVA by including baseline values of 25(OH)D and iPTH as a covariate in the analysis where a significant difference in baseline was present, while repeated measures ANOVA was done otherwise. The correlation analysis by Spearman rank coefficient analysis explored the relationship between baseline 25(OH)D and other parameters like baseline iPTH, BMI, body fat percentage, serum calcium, ALP, and 1,25(OH)2D levels. Multiple linear regression analysis was used to investigate the relationship between change in serum 25(OH)D with factors like age, gender, body mass index, body fat percentage, type of intervention (calcifediol or cholecalciferol group), baseline serum 25(OH)D levels, and ALP. Missing data was excluded during the analysis.
Results
A total of 140 participants were screened, including 70 each in the calcifediol and cholecalciferol groups. Out of 70 participants in each group, 8 were excluded from the calcifediol group- 1 due to chronic kidney disease, 3 due to underlying renal stones/nephrocalcinosis, 1 due to pregnancy and 2 due to malabsorption. In the cholecalciferol group, 15 were unwilling to participate further, 5 got excluded due to underlying renal stones, nephrocalcinosis, 3 due to chronic steroid intake, 3 due to malabsorption, 2 due to chronic kidney disease, 1 due to chronic liver disease. After application of inclusion and exclusion criteria, 62 were included in the calcifediol group and 41 in the cholecalciferol group (Figure 1). Of the 62 participants in the calcifediol group, 16 dropped out for various reasons between baseline visit (visit 1) and 3 months (visit 2). Similarly, out of the 41 subjects in the cholecalciferol group, 4 dropped out during follow-up between baseline visit and 3 months (Figure 1). Only the participants who received intervention for 6 months (visit 3) and completed the follow-up were included in the final analysis.
Fig. 1. Inclusion and follow-up of subjects into the study.
The baseline parameters of the subjects in the two groups are shown in Table 1. The mean age of the subjects in the calcifediol group was 41.4 ± 10.1 years, while it was 41.8 ± 14.6 years in the cholecalciferol group. Both groups had a female preponderance (63.5% in the calcifediol and 56.1% in the cholecalciferol group).
Table 1. Baseline clinical and biochemical parameters of subjects in both groups (Mean ± SD)
Normally distributed data is depicted as mean ± standard deviation. Non-normally distributed data is shown as median (Interquartile range) BMI = Body Mass Index, 25 OH D = 25 hydroxy vitamin D, iPTH = intact Parathyroid hormone, Ca = calcium, P = Phosphate, ALP = Alkaline Phosphatase, 1,25 (OH)2 D = 1,25 dihydroxy vitamin D, U Ca/Cr= urinary calcium creatinine ratio, βCTX = Beta C-terminal cross-linked telopeptide of type I collagen, P1NP = Procollagen type 1 N-terminal propeptide.
The serum 25(OH)D levels exhibited a persistent upward trend over time (p < 0.001) within both treatment cohorts. Serum 25(OH)D significantly rose at the visit 2 (3 months) and continued to increase till the end of follow-up (visit 3 = 6 months). Commensurate with changes in serum 25(OH)D levels, iPTH levels decreased over the study period (p < 0.001) across both groups. Serum iPTH significantly reduced from baseline to 3 months, and showed a further decline till six months, which was non-significant. There was a significant increase in 1,25(OH)2D from baseline to 3 months, without any substantial changes thereafter at 6 months (p < 0.001) Figure 2. Serum ALP showed a significant reduction only from 3 months to 6 months but not in the initial half (p = 0.016). There were no significant differences in serum calcium (p = 0.33), phosphorus (p = 0.065), urinary calcium creatinine ratio (p = 0.792) Figure 3, P1NP (p = 0.214), βCTX (p = 0.144) and serum creatinine (p = 0.059) at 3 or 6 months in either group (p > 0.05) Figure 4.
Fig. 2. Change in serum 25(OH)D, iPTH, 1,25 (OH)2D, and ALP with each visit (Baseline, three months, and six months) in calcifediol capsule and cholecalciferol sachet groups.
Asterisk (nmol/L = 2.5 x ng/dl) denotes significant differences within subjects between those visits. Blue indicates calcifediol capsule group and brown indicates cholecalciferol sachet group. Visit 1 was baseline visit, visit 2 was 3 month follow up visit and visit 3 was 6 month follow up visit.
Fig. 3. Change in serum calcium, serum phosphorous, urinary calcium creatinine and creatinine with each visit (Baseline, three months and six months) in calcifediol capsule and cholecalciferol sachet groups.
Asterisk denotes significant differences within subjects between those visits. Blue indicates calcifediol capsule group and brown indicates cholecalciferol sachet group. Visit 1 was baseline visit, visit 2 was 3 month follow up visit and visit 3 was 6 month follow up visit.
Fig. 4. Change in P1NP and βCTX with each visit (Baseline, three months, and six months) in calcifediol capsule and cholecalciferol sachet groups.
Blue indicates calcifediol capsule group and brown indicates cholecalciferol sachet group. Visit 1 was baseline visit, Visit 2 was 3 month follow up visit and visit 3 was 6 month follow up visit.
The change in median values of each of the biochemical parameters from enrolment into the study till the end of follow-up is shown in Table 2. The median rise in 25(OH)D was 574% in the calcifediol and 355% in the cholecalciferol group, with a decrease in iPTH of 46.9% in the calcifediol group and 44.9% in the cholecalciferol group. The median ALP was reduced by 14.7% in the calcifediol group and 7.1% in the cholecalciferol group. The median spot urinary calcium creatinine ratio decreased by 23.8% in the calcifediol group and 19.3% in the cholecalciferol group. The median 1,25(OH)2D levels increased by 15.3% in the calcifediol group and 32.4% in the cholecalciferol group at the end of 6 months.
Table 2. Median values and Interquartile range of the biochemical parameters in each visit with supplementation
25 OH D = 25 hydroxy vitamin D, iPTH = intact Parathyroid hormone, Ca = calcium, P = Phosphate, ALP = Alkaline Phosphatase, U Ca/Cr = urinary calcium creatinine ratio, βCTX = Beta C-terminal cross-linked telopeptide of type I collagen, P1NP = Procollagen type 1 N-terminal propeptide, 1,25 (OH)2 D = 1,25 dihydroxy vitamin D.
The 25(OH)D increased from baseline (visit 1) to 3 month (visit 2) follow up in 100% of subjects in both groups but further continued to increase from follow up at 3 months to 6 months (visit 3) in 71.8% in the calcifediol group and 80.5% in the cholecalciferol group. The serum 25(OH)D values were greater than 75 nmol/L in 35 out of 62 subjects (56.4%) at the end of visit 2 and 41 out of 46 subjects (89.1%) at the end of visit 3 in the calcifediol group. The serum 25(OH)D values were greater than 75 nmol/L in 37 out of 41 subjects (90.24%) at the end of visit 2 and in 36 out of 37 subjects (97.29%) at the end of visit 3 in the cholecalciferol group. The serum 25(OH)D values were greater than 250 nmol/L in 13 out of 46 subjects (90.24%) in the calcifediol group and 7 out of 37 subjects (97.29%) in the cholecalciferol group at the end of the follow up. The serum 25(OH)D values were greater than 250 nmol/L in 1 out of 62 subjects (1.62%) at the end of visit 2 and 13 out of 46 subjects (28.2%) at the end of visit 3 in the calcifediol group. The serum 25(OH)D values were greater than 250 nmol/L in none of the patients at the end of visit 2 and 7 out of 37 subjects (18.92%) at the end of visit 3 in the cholecalciferol group. For each ng/ml increase in serum 25(OH)D, calcifediol is 4.6 times more potent than cholecalciferol.
Notably, no significant differences were observed between the participants in the calcifediol group as compared to the cholecalciferol group in terms of increase in serum 25(OH)D (treatment*time interaction p = 0.91). No substantial differences were detected between the treatment modalities in terms of decrease in serum iPTH (group*time interaction p = 0.54). The calcifediol group was associated with a significantly greater decline in serum ALP than the cholecalciferol group (p = 0.009). There was no significant difference between the two groups in terms of change in serum 1,25(OH)2D (p = 0.286), and for the rest of the biochemical parameters, there was no significant change in parameters with treatment, and hence between-group differences were not calculated.
In terms of adverse effects, no subject developed significant side effects that led to the discontinuation of therapy. The albumin-adjusted calcium values were normal for all individuals at baseline and in follow-up. In the calcifediol group, the spot urinary calcium creatinine was more than 4 mg/kg/g in 3 out of 46 subjects (6.5%) and more than 0.2 mg/mg in 8 out of 46 subjects (17.4%) at the end of visit 3. In the cholecalciferol group, it was more than 4 mg/kg/g in 2 out of 37 (5.4%) subjects and more than 0.2 mg/mg in 5 out of 37 subjects (13.5%) at the end of visit 3. The details of the urinary calcium creatinine ratio at each visit with different cutoffs are mentioned in Table 3. On ultrasonography of the kidney done for all subjects, there was no new development of nephrolithiasis or nephrocalcinosis in any subject.
Table 3. Prevalence of adverse events in both groups throughout the study
*p value calculated between groups at final visit. NS = not significant.
Correlation analysis revealed an inverse correlation between baseline 25(OH)D and iPTH levels (Spearman’s rho = −0.243, p = 0.013) and no significant association with BMI, body fat percentage, serum calcium, ALP and 1,25(OH)2D concentrations. Multivariate linear regression analysis was carried out to investigate the relationship between change in serum 25(OH)D with factors like age, gender, BMI, body fat percentage, type of intervention (calcifediol or cholecalciferol), baseline serum 25(OH)D and ALP concentrations. The R2 for the model was 0.302 with a p-value of 0.002. There was a significant relationship between baseline serum 25(OH)D levels (β = −0.288, p < 0.01) and baseline ALP levels (β = 0.112, p = 0.03) with change in serum 25 OHD levels.
Discussion
The present study aimed to evaluate the safety and efficacy of replacement with daily 25 µg calcifediol capsules versus 100 µg (4000 IU) cholecalciferol sachets over six months in apparently healthy individuals with vitamin D deficiency. It also aimed to establish dose equivalence between the above two forms. There was a significant rise in serum 25(OH)D levels and 1,25(OH)2D levels, with a significant decline in serum ALP and serum iPTH levels. Both the formulations did not have any significant difference in follow-up between the two groups, except for a greater reduction in ALP with calcifediol as compared to cholecalciferol. Furthermore, there was no incident hypercalcaemia or significant change in spot urine calcium creatinine ratio over follow-up as adverse effects. There was also no development of renal stones in either group. To the best of our knowledge and literature search, this study was the first to compare the safety and efficacy of 25 µg calcifediol capsule with 100 µg (4000 IU) cholecalciferol sachets over a long-term follow-up period of 6 months.
We observed a significant increase in serum 25(OH)D concentrations in both groups, with a continuing significant increase from baseline till the end of follow-up in both groups. There was also a significant increase in serum 1,25(OH)2D concentrations and a significant decline in serum iPTH in both groups, but this was only observed in the first 3 months. There was no significant change in either 1,25(OH)2D or PTH beyond 3 months, despite progressive rise in circulating 25(OH)D levels. There being no significant difference between the two groups in terms of change in serum 25(OH)D levels despite dose ratio of 1:4 is consistent with the findings of previous studies showing calcifediol to be around 2.5–5 times more potent than cholecalciferol at various dose ranges. Furthermore, calculating potency for each ng/ml increase in serum 25(OH)D, we found calcifediol to be 4.6 times more potent as compared to cholecalciferol. This is in line with available literature.(Reference Jodar, Campusano and de Jongh7,Reference Vaes, Tieland and Regt9–Reference Wittwer21)
There was a significant decline in serum ALP from 3 months to 6 months (p = 0.016) with marginal decline in the initial 3 months. Previous studies from Gupta et al have also shown no significant change in ALP levels till 3 months which is concurrent with findings in the present study. Calcifediol capsules were slightly more efficacious than cholecalciferol sachets in the reduction of serum ALP levels, likely due to the more potent efficacy of calcifediol capsule to activate Vitamin D Receptor (VDR) compared to cholecalciferol sachets. However, whether this translates into superior clinical efficacy is not certain as the sample size is quite small to imply any significant difference in day-to-day clinical use.(Reference Kunz, Beck, Schoop and Etheve16,Reference Das, Holick and Sachdeva22,Reference Davies, Mawer and Krawitt23) The change in bone turnover makers were not significant even though ALP changed significantly and this could likely be due to small sample size.
Multiple regression analysis revealed that the increase in serum 25(OH)D levels was dependent on baseline 25(OH)D levels and it was independent of age, gender, BMI, body fat percentage or type of intervention. All participants included in our study had baseline serum 25(OH)D levels below 75 nmol/L.
On post hoc subgroup analysis based on baseline vitamin D status, dividing participants into severe deficiency (<30 nmol/L), and moderate deficiency (30–75 nmol/L) responses at discrete time points differed between these subgroups were assessed on independent-samples t-tests comparing serum 25(OH)D levels at 3 and 6 months between the two treatment groups. At baseline and at the 3-month follow-up each subgroup showed, participants with severe deficiency (<30 nmol/L) had significantly higher serum 25(OH)D levels in the cholecalciferol group compared to the calcifediol group (mean difference = 11.46 nmol/L, p = 0.017). Among those with moderate deficiency, the calcifediol group had a higher level, though this difference was not statistically significant (p = 0.207).
At 6 months, mean serum 25(OH)D concentrations were similar between groups in both the severe and moderate subgroups (severe: p = 0.924; moderate: p = 0.647), indicating comparable long-term efficacy across both treatment arms, regardless of baseline severity.(Supplementary table)
Previous studies done with cholecalciferol have a similar finding where post-treatment rise in 25(OH)D levels were based on baseline 25(OH)D levels.(Reference Shab-Bidar, Bours and Geusens4,Reference Das, Holick and Sachdeva22–Reference Paccaud, Rios-Leyvraz and Bochud30) In the present study, we now know that the rise in serum 25(OH)D was directly proportional to baseline serum 25(OH)D levels in both calcifediol and cholecalciferol groups. We had also shown similar findings in our last study where the increase in serum was directly proportional to the baseline serum 25(OH)D.(Reference Das, Holick and Sachdeva22)
While previous systematic reviews and meta-analysis have found lower increase in 25(OH)D levels in obese subjects as compared to normal subjects, our present study found rise in 25(OH)D levels to be independent of Body mass index of the subjects.(Reference Minisola, Cianferotti and Biondi17) Due to the smaller sample size in present study no definite conclusion could be made.
Regarding adverse events, there was no hypercalcaemia in both groups despite relatively higher doses of 25 µg of calcifediol capsules and 100 µg (4000 IU) of cholecalciferol sachets given daily over six months. There was also no significant change in spot urine calcium creatinine ratio despite follow-up over six months and no significant difference in the development of renal stones between the two groups. 6.52% of subjects in the capsule group vs 5.41% of subjects in the sachet group had hypercalciuria at the final visit, and there was no significant difference between the two groups. Moreover, the utility of spot urinary calcium creatinine ratio is also unknown. Previous studies have found a correlation of only 64% between random urinary calcium creatinine ratio and 24-hour urinary calcium, implying that collection of 24-hour urinary calcium is superior but it was not possible in present study due to logistic reasons.(Reference Petkovich, Melnick and White18)
The strengths of our study are that it provides the first evidence to compare the safety and efficacy of 25 µg of calcifediol capsule and 100 ug (4000 IU) of cholecalciferol sachets over a relatively long period of 6 months with a relatively sizeable number of participants and a rigorous assessment of hypercalcaemia and hypercalciuria (using urine calcium excretion and ultrasonography of the kidneys) during follow-up to gauge adverse effects. The efficacy of both drugs was similar, and there was no difference in terms of hypercalcaemia, hypercalciuria or development of renal stones over a follow up of 6 months. The study also adds to growing evidence in the literature of calcifediol capsules being more potent than cholecalciferol sachets by a factor of around 4 at 25 µg of calcifediol and 100 µg (4000 IU) of cholecalciferol. However, we do acknowledge certain limitations such as an open-label, non-randomised study design, unequal number of participants, number of dropouts and differences at baseline and inability to carry out 24 hour urinary calcium creatinine ratio.
Conclusion
This study establishes the safety and efficacy of correcting vitamin D deficiency with daily 25 µg calcifediol capsules as an alternative to cholecalciferol sachets. It also reconfirms the higher potency of calcifediol capsules compared to cholecalciferol sachets.
Supplementary material
To view supplementary material for this article, please visit https://doi.org/10.1017/jns.2025.10064.
Data availability statement
Data available on request from the corresponding author.
Acknowledgments
None.
Author contributions
Conceptualisation, P.D. and R.K.M; methodology, R.S., P.D., R.K.M.; formal analysis, R.S., R.K.M.,S.M,D.B; investigation, P.D., R.K.M., R.S.; writing — original draft preparation, R.S., L.D, P.D.; writing — review and editing, R.S., S.M, L.D, P.D., R.K.M., M.H.; visualisation, R.S.,P.D, S.M; supervision, M.H., R.K.M., P.D.; funding acquisition, R.K.M., M.H. P.D, S.M, RKM; Re-writing.
All authors have read and agreed to the published version of the manuscript.
Funding
The Dishman Carbogen Amcis Ltd. generously provided calcifediol capsules.
Competing interests
M.H. reported grants from Dishman Carbogen Amcis Ltd. And Solius Inc., consultant, personal fees from Biogenia Consultant, Sanofi Speaker Bureau, Faes Farma Consultant, non-financial support from Ontometrics Consultant, Hyper Hypera Pharma Speaker Bureau, Pulse Pharmaceuticals pvt, Ltd. Speaker Bureau, and Menarini India Private Limited. No other authors have conflict of interest.
Ethical approval
This study was conducted according to the guidelines laid down in the Declaration of Helsinki and all procedures involving human subjects/patients were approved by the Institutional Ethics Committee of PGIMER (IEC-03/2023-2687). Written informed consent was obtained from all subjects/patients.
Informed consent statement
Informed consent was obtained from all subjects involved in the study. Written informed consent has been obtained from the subject(s) to publish this paper.
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