Calcipotliol 
Review 
CALCIPOTRIOL - A VITAMIN D3 ANALOGUE 
(MC 903) IN THE TREATMENT OF PSORIASIS 
VULGARIS: A REVIEW 
R. Čeovic, J. Lipozenčic and A. Pašic 
SUMMARY 
Calcipotriol, a vitamin D3 analogue, is an effective and well tolerated topical therapy of mild and medium 
intensive plaque psoriasis. Calcipotriol reduces epidermal celi proliferation and enhances differentiation in 
lesional skin. Calcipotriol ointment, applied twice daily, may be more effective than betamethazone valerate 
and dithranol. In combination with other antipsoriatic treatments (UVB, PUV A, Cyclosporin), it is used in 
therapy of severe psoriasis. The most frequently occurring adverse events are lesional and perilesional skin 
irritations. There is no risk of hypercalcemia if calcipotriol is used in recommended doses not more than 100 
g weekly. Calcipotriol ointment is today an effective and safe alternative therapy for psoriasis vulgaris in 
children. For the treatment of scalp psoriasis a calcipotriol solution can be used. In this article, the literature 
is reviewed and different calcipotriol therapeutic modalities are discussed. 
KEY WORDS 
vitamin D, calcipotriol, plaque psoriasis, review 
Calcipotriol is a vitamin D3 analogue, which was 
used for the first tirne in dermatology in 1985 when 
a group of Japanese researchers found that in a 
patient with senile osteoporosis, associated psoriatic 
lesions disappeared unexpectedly during the treatment 
with oral active vitamin D3 (1, 2). 
Some facts about vitamin D3 and skin are well 
known: 
• cholecalciferol - vitamin D3 is synthesized in 
the epidermis under the effect of UVB light from 
7-dehydrocholesterol 
• hypocalcemia can cause exanthemas of psoriatic 
acta dennatovenerologica A .P.A. Vol 7, 98, No 2 
type (as a result of deficiency of vitamin D in food, 
deficiency of UV light or hypoparatiroidism) (3, 4, 
5, 6). 
• specific receptors for calcipotriol have been found 
in skin (7). 
The skin has an important role in metabolism of 
vitamin D3. 
Under the effect of UVB light 7-dehydrocholesterol 
changes in the epidermis in cholecalciferol. .The 
cholecalciferol produced in such way is carried to 
the !iver for the 25-hydroxylisation and 25 hydroxi-
calciferol is synthesized (25 OHD3). It is further 
67 
Calcipotriol 
hydroxilized with one hydroxilization in the kidneys 
in 1-alfa-25-dihydroxy-D3, calcitriol, a metabolite of 
vitamin D3, which is 100 times more active than 
vitamin D3. In vitamin D3 deficiency the skin is 
capable of producing vitamin 1,25 (OH) D3. 1-
hydroxylization is stimulated by deficiency of calcium 
and phosphates and by parathyroid hormone. 
Specific receptors for 1,25 (OH) D3 have recently 
been found not only in the skin but also in other 
tissues as muscle, pancreas (7, 8, 9) and in some 
tumors (10). Receptor-mediated effects on celi 
proliferation and celi differentiation have been observed 
(11, 12, 13). 
The most characteristic feature of psoriatic lesions 
is an abnormally increased proliferation of epidermal 
keratinocytes as well as an incomplete differentiation 
(14). Overall, in patients with psoriasis the transit 
tirne of epidermal cells is reduced from 28 to 
7-dehydrocholesterol 
1 skin 
~ (UV light) 
Cholecalciferol (03) 
liver 
25-hydroxicholecalciferol 
kidney 
(caused by 
parathyroid 
hormon and low 
level of phosphate 
in blood) 
1,25-dihydroxicholecalciferol 
Stimulates 
Ca resorption 
from intestine 
(primary effect) 
/~ Stimulates 
Ca mobilization 
in bones 
(secondary effect) 
Fig. l. Schematic presentation of vitamin D metabolism. 
Mardešic, D., Pedijatrija, Metabolism of vitamin D, 
Zagreb, Šk. Knjiga, 1991; 244. 
acta de,matovenerologica A.P.A. Vol 7, 98, No 2 
approximately 4 days, the epidermis appears about 
3 to 5 times thicker than normal (15). 
Calcitriol markedly suppresses proliferation and 
enhances differentiation of epidermal keratinocytes 
(14) but the use of highly active vitamin D3 derivatives 
to control celi proliferation and to promote celi 
differentiation is limited by their potent effects on 
calcium metabolism. Hypercalcemia is induced by 
oral systemic doses higher than a few mg per day, 
and topical application is complicated by the risk of 
increased transdermal absorption of the active com-
pound in areas of psoriatic skin lesions (16). 
It has therefore been necessary to develop new 
vitamin D3 analogues with potent effects on celi 
proliferation and celi differentiation, but with a 
lower risk of inducing the classical vitamin D associated 
side effects: hypercalciuria, hypercalcemia and induction 
of bone resorption (13) . 
As a result of chemical and pharmacological 
research, a new vitamin D3 analogue calcipotriol 
(MC 903) has been developed. 
Calcipotriol is a colorless crystalline substance 
with a molecular weight of 412.62, melting point of 
166-8°C and a summation formula of C
27
H
4
0
3 
(Fig. 
2). Calcipotriol demonstrated effects on celi pro-
liferation and differentiation similar to those of 
calcitriol in many in vitro experiments (17). So it 
was expected from calcipotriol to exhibit cellular 
antiproliferative and differentiation enhancing effects 
in vivo. 
In patients with chronic plaque psoriasis calcipotriol 
influences ali three main mechanisms of psoriasis 
pathogenesis. It shows antiproliferative, anti-inflamma-
tory effects and enhances differentiation in lesional 
skin (16). 
Calcipotriol is 100 to 200 times less potent than 
calcitriol in regulating the in vivo calcium metabolism 
in rats. Calcipotriol 1 and 10 mg/kg/day administrated 
intraperitoneally to rats for 7 days did not significantly 
affect serum and urinary calcium levels and calcium 
content of tibial metaphysis. Conversely, calcipotriol 
100 mg/kg/day and calcitriol 0,5 mg/kg/day significantly 
altered these parameters (17). 
EFFECTS ON IMMUNOLOGICAL 
AND INFLAMMATORY MEDIATORS 
Effects of calcipotriol on interleukins 1 and 6 ·(IL-
1 and IL-6), immunological and inflammatory mediators 
in the pathogenesis of psoriasis require special atten-
tion, but are stili not fully explained. 
69 
In vitro calcipotriol inhibited mouse thymocite proli-
feration in response to human IL-1 in a dose 
dependant fashion (18). 
In the patients with plaque psoriasis, calcipotriol 
ointment 50 mg/g: 
• reduces the accumulation of polymorphonuclear 
leukocytes during the first week of treatment (19) 
• reduces the number of epidermal cells after two 
weeks of treatment (19), and 
• after faur weeks treatment, the number of keratin-
16-positive cells and the number of T lymphocytes 
decreased significantly (19). 
The number of CD 14 cells and Langerhans cells 
remained unaffected during the treatment (19, 20, 
21, 22). 
The role of vitamin D3 in vivo studies can be 
concluded: an influence on epidermal proliferation 
and accumulation of polymorphonuclear leukocytes 
is an early effect, whereas the modulation of the 
number of T cells, monocytes and macrophages are 
late effects (23). 
DOSAGE AND ADMINISTRATION 
One gram of calcipotriol ointment contains 50 mg 
calcipotriol. It should be applied sparingly to the 
affected skin twice a day, no more than 100 g per 
week. A higher dose may be associated with an 
increased risk of hypercalcemia. Initially it was 
recommended that the course of calcipotriol treatment 
should not exceed 6 weeks, but later on clinical 
studies which lasted 12 months have shown that it 
was an effective and well tolerated preparation. 
Today calcipotriol is accepted as a treatment, which 
can be used far months without risk of lasting skin 
or systemic side effects when the dosage is lower 
than 60-100 mg per week (24). 
TOLERABILITY 
In the course of clinical trials, it was shown that 
the most common adverse effects were: lesional and 
perilesional skin irritation ( qualified by patients as 
burning, itching and stinging), erythema, scaling and 
peeling of the skin ( overall incidence 8,8 to 19,5%) 
(25). 
Calcipotriol ointment should not be applied to 
psoriatic lesions on the face because it may give 
rise to irritation (25, 26). Facial dermatitis caused 
70 
Calcipotriol 
HO .-· OH 
HO 
Fig. 2. Structural formula of calcipotriol 
by calcipotriol ointment was generally mild and 
transparent in nature (14, 27). Often the facial 
dermatitis is caused by unintentional transfer of 
calcipotriol ointment from hands to the face, therefare 
careful handwashing after use of the ointment is 
recommended (24, 28) . 
In a few clinical trials with a very large number 
of patients treated with calcipotriol ointment 50 mg/ 
g twice daily tata! serum calcium levels were not 
significantly altered (29, 30, 31). 
There are stili no reports about using calcipotriol 
ointment during pregnancy. Although studies in 
experimental animals have not shown any teratogenic 
effect, it is not advisable for pregnant women to 
use calcipotriol ointment. 
CALCIPOTRIOL OINTMENT IN 
CHILDHOOD PSORIASIS 
Clinical trials far assessing the safety and efficacy 
of calcipotriol use far psoriasis vulgaris in children, 
showed no serious side effects, including those relating 
to calcium and bone metabolism, hematological and 
biochemical parameters. 
Calcipotriol ointment bas proved to be an effective, 
well-tolerated, acceptable and safe alternative therapy 
far psoriasis vulgaris in children (32, 33, 34). 
The efficacy of calcipotriol in psoriasis can not be 
compared to systemic antipsoriatic treatments, but 
the simultaneous use of both improves the therapeutic 
results, allows lower doses than those used iri single 
agent therapy and consequently reduces the risk of 
side effects arising from systemic antipsoriatic trea-
tment. 
acta derrnatovenerologica A.P.A. Vol 7, 98, No 2 
Calcipotriol 
COMBINATIONS OF V ARIOUS OTHER 
TREATMENTS WITH CALCIPOTRIOL 
Calcipotriol + UVB 
Clinical trials with this combined therapy showed 
that calcipotriol enhances UVB therapy (35, 36, 37, 
38, 39). Calcipotriol ointment should never be applied 
immediately before the application of UVB light 
because it can decrease the minimal erythema dose 
(MED) (40, 41, 42). When applied after the UVB 
therapy, calcipotriol did not show any adverse inter-
actions, neither to artificial UVB light nor to sun 
exposure (40, 41). 
Calcipotriol + PUV A 
PUV A therapy is one of the most effective 
treatments for psoriasis, but high-dose or long-term 
PUV A treatment increases the risk of cutaneous 
malignancies, especially basalioma ( 43, 44, 45). Combi-
nation of calcipotriol ointment and PUV A reduces 
total UV A dose required for clearance of skin 
lesions and shows no interactions if calcipotriol is 
applied after the application of UVA ( 41, 42, 46, 
47). 
Calcipotriol and cyclosporine 
Calcipotriol was shown to augment the immuno-
suppressive effect of cyclosporine on interleukin 2 
secretion ( 48, 49, 50). Taking synergistic effect of 
calcipotriol and cyclosporine into account, severa! 
studies were conducted in order to explore the 
possibilities of this combination with the objective 
of reducing side effects, especially renal toxicity, by 
decreasing the doses of cyclosporine (51, 52). The 
authors concluded that the combination of calcipotriol 
and cyclosporine enhanced the efficacy of antipsoriatic 
treatment, improved the risk-benefit ratio, and 
permitted the use of lower dosage of cyclosporine 
(52, 53). 
Calcipotriol and oral retinoids 
There is only one publication with quantitative 
data on combined therapy with calcipotriol and oral 
retinoids where authors concluded that calcipotriol/ 
acitretin combination produced a significantly better 
therapeutic response with a lower cumulative acitretin 
dose (54). 
acta dennatovenerologica A.P.A. Vol 7, 98, No 2 
We did not find a report on combined therapy 
with calcipotriol and methotrexate. 
Calcipotriol solution 
For the treatment of scalp psoriasis, a solution of 
calcipotriol (50 mg/ml) is available. It should be 
used twice daily; one to two drops of the solution 
to a psoriatic lesion of the approximate size of a 
coin, not exceeding 60 ml per week. In a double 
blind, four-week clinical tria!, calcipotriol solution 
showed to be more effective than the vehicle alone 
(55). In double blind, four-week long clinical study, 
calcipotriol solution (50 mg/ml) was compared with 
betamethazone-17-valerate solution (1 mg/ml) in pa-
tients with scalp psoriasis. Although application of 
calcipotriol solution resulted in significant improvement, 
betamethazone-17-valerate solution was more effective 
(24, 56). Possible side effects of calcipotriol solution 
are irritation of the face and scalp; it is recommended 
to avoid contact of the solution with eyes and facial 
skin. In case of thick scales, the therapy should 
begin with salicylic acid and continued with calcipotriol 
solution. Salicylic acid should not be used with 
calcipotriol solution at the same tirne because it can 
inactivate calcipotriol. 
Calcipo triol 
in treatment of nail psoriasis 
Treatment of nail psoriasis is difficult, long-lasting 
and often without success. Some reports, which 
suggested that nail psoriasis might respond to topical 
calcipotriol, were therefore welcomed. Kokelj et al. 
treated 7 patients with calcipotriol ointment twice 
daily for 3 months and five of them experienced an 
improvement of their psoriasis (57). We also suggested 
to our patients who used calcipotriol for their skin 
lesions to apply calcipotriol ointment around the 
nail area twice daily: preliminary results were consi-
dered as satisfactory. 
Other therapeutic 
modalities of calcipotriol 
Calcipotriol could be used for treatment of skin 
disorders other than plaque psoriasis. The vitamin 
D3 receptors have been detected in various celi 
types in the skin including keratinocytes, Langerhans 
cells (58), melanocytes (59), fibroblasts (60) and 
endothelial cells (61). There are few reports about 
71 
Calcipotriol 
using calcipotriol ointment in the treatment of 
intertriginous psoriasis (62), palmoplantar (63) and 
pustular psoriasis (64, 65), Reiter's syndrome (66), 
pityriasis rubra pilaris (67) and disorders of keratini-
zation (68, 69, 70, 71). Recent reports suggest that 
the hyperproliferative variants of ichthyoses and 
keratodermas may respond to topical calcipotriol 
ointment, although the use can be limited due to 
theoretical risk of hypercalcemia. Namely, disorders 
of keratinization involve usually large areas of skin 
and it is easy to assume that patients can exceed 
the recommended weekly dose of 100 g of calcipotriol. 
Other mentioned diseases (intertriginous and pustular 
psoriasis, Reiter's syndrome, pityriasis rubra pilaris) 
responded positively to calcipotriol but more studies 
should be done to corroborate these preliminary 
results on a small number of patients (72). 
CONCLUSION 
Calcipotriol, a vitamin D3 analogue, is today a 
well-established and widely used effective treatment 
for mild and medium plaque psoriasis. In combination 
with other therapeutic modalities it is successfully 
used also in severe cases of psoriasis. Topically applied, 
calcipotriol has a low hypercalcemic potential and in 
contrast to all other available antipsoriatic therapies 
( to pica! corticosteroids, retinoids, rnethotrexate, and 
cyclosporin), it does not show a risk of serious 
adverse events. A limitation of treatment with calcipotriol 
is irritation of lesional and perilesional skin. 
Today, vitamin D derivatives have already an 
important place in treatment of psoriasis, but it 
seems to be even more promising for the future. 
Namely, new analogues are available which seem to 
be more effective than calcipotriol due to altered 
chemical structure. 
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AUTHORS' ADDRESSES 
Romana Čeovic MD, dermatologist, Dpt Dermatology, Clinical Medica! Center, Šalata 4, 
10000 Zagreb, Croatia 
Jasna Lipozenčic MD, PhD. professor and head of the department, same address 
Aida Pašic MD, consultant dermatologist, same address 
acta dennatovenerologica A.P.A. Vol 7, 98, No 2 77