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Rationality of Vitamin D & Calcium Supplements and

Available Formulations in Indian Scenario: A Study on

Knowledge, Attitude and Prescribing Practice of Doctors in

Tertiary Care Teaching Hospital

By

Archana.V *, Rubdeep Singh Bindra *, Rajeev Mishra *

S.V.Desai**

Department Of Pharmacology

Sumandeep Vidyapeeth University

Piparia, Vadodara, Gujarat.

* Second year residents

** Professor


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Abstract

Introduction:

The present study was undertaken to analyze formulations containing Vitamin D or/and Calcium

currently available in Indian Market, with regard to their rationality and cost-effectiveness, and

also to study the knowledge, attitude and prescribing practice of doctors in a tertiary careteaching hospital in this regard.

Methodology:

July-September 2009, issue of drug today was referred for listing formulations containing

Vitamin D or Calcium or both. They were analyzed for the type of Vitamin D or Calcium salt,

the amount, indications and daily treatment cost. One hundred prescriptions containing

formulations of Vitamin D or Calcium or both presented to hospital pharmacy were analyzed.

Thirty seven doctors from the departments of Medicine, Pediatrics, Orthopedics and Obstetrics

and Gynecology were interviewed to study knowledge, attitude and prescribing behavior with

regard to Vitamin D and Calcium

Results:

44% of multivitamin formulations contained Vitamin D or/and Calcium. Of the 595 formulations

containing Vitamin D or/and Calcium, 90% had both, the commonest being combination of

calcium carbonate with Vitamin D3 (48%)/Alfacalcidol (19%). Calcium and vitamin D wereprescribed without justification in 62% and 79% respectively. Of the indications listed by

doctors, only 51% could be considered rational. Two thirds of the doctors believed that organic

calcium carbonate has higher bioavailability than inorganic calcium carbonate. Whereas,

preparations containing organic calcium carbonate were 8-9 times costlier than the inorganic

ones.

Discussion and conclusion:

Irrational use of Vitamin D & Calcium, lack of correct knowledge and disregard for treatment

cost, even in a teaching institution, is a matter of concern.

Keywords

Vitamin D, Calcium, organic calcium (oyster), pregnancy, lactation, postmenopausal women,

osteoporosis


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Introduction

Vitamin D is a fat-soluble vitamin that is made available to the body by either sun (ultraviolet

light) exposure or dietary intake. There are 2 molecules that make up vitamin D: ergocalciferol

(D2) and cholecalciferol (D3).[1] Ultraviolet B (UVB) radiation is absorbed by the skin and

converts 7-dehydtocholesterol to vitamin D3.[2]

Vitamin D3 then goes into the capillary bed,

where it binds to vitamin D binding protein (DBP). Vitamin D2 and vitamin D3 are also ingestedthrough the diet from fortified milk, fatty fish (salmon), and fortified cereals. Once ingested, they

are incorporated into chylomicrons. The chylomicrons are transported through the lymphatic

system and then are released into venous circulation, where vitamin D is bound to lipoproteins

and DBP.[2]

Both vitamin D from the sun and diet then enter the liver and are converted to 25-

hydroxyvitamin D [25(OH)D3] (calcidiol);[2] 25(OH)D3 (calcidiol) is the major circulating form

of vitamin D and is used to determine vitamin D status. To become biologically active, it

requires additional hydroxylation in the kidneys to form active 1, 25-hydroxyvitamin D [1,

25(OH) 2D] (calcitriol); however, 1, 25(OH) 2D is not used to determine vitamin D status

because it circulates at 1000 times less concentration than 25(OH) D3 and it has a half life of 6

hours in comparison to 2 weeks for 25(OH) D3.[2]

1, 25-Dihydroxy vitamin D (vitamin D) is a hormone with a number of pharmacological and

physiological effects, first demonstrated as the effect to cure osteomalacia and later as a hormone

with effects related to mineral homeostasis, cell differentiation, immunology, vascular

calcification and ageing.[3-5]

Vitamin D has its greatest effect on the maintenance of adequate levels of serum calcium.

Calcitriol works with parathyroid hormone to maintain adequate calcium and phosphorus levels

in the blood. When serum calcium is too low, parathyroid hormone stimulates calcitriol to act to

increase the intestinal absorption of calcium, increase the resorption of calcium by the kidneys,

and stimulate the release of calcium from the bone. In response to elevated serum calcium,

calcitriol decreases intestinal absorption and stimulates bone to take up calcium, decreasing

serum calcium.[7]

Deficiency occurs when people do not have adequate exposure to UVB rays or adequate dietaryintake. According to the National Institutes of Health (NIH), 10 to 15 minutes of direct sunlight

at least twice a week to the face, arms, hands, or back is sufficient to maintain optimum serum

Vitamin D levels.[7]

People with darker skin pigmentation have a reduction of synthesis by 99% because the UVB

rays are being absorbed by melanin. There is a reduction of 7-dehydrocholesterol in the skin as

aging occursonly 25% of vitamin D3 is synthesized in a 70-year-old.[8]

Therefore, people with

darker skin, and elders, need to ingest more vitamin D in their diets.


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People who are obese also have a more difficult time maintaining optimum vitamin D levels.

Vitamin D is fat soluble and therefore easily stores in adipose tissue. This storage results in

decreased vitamin D in the bloodstream. It has also been found that release of vitamin D from the

skin into circulation is altered in obese women.[1]

Due to this information, people who are obese

should try to obtain more vitamin D from their diet. Intestinally absorbed ergocaliciferol (D2) is

most bioavailable in people with obesity.[1]

Vitamin D deficiency is determined by serum 25(OH) D levels. Recommended levels, according

to textbooks, of vitamin D can vary from 9 to 38 ng/mL (20-110 nmol/mL).[9] However,

according to recent research and recommendations from vitamin D experts, ideal serum levels

are between 30 and 60 ng/mL. Insufficiency is 25 to 30 ng/mL, rickets or osteomalacia is evident

at less than 20 ng/mL, and frank insufficiency is less than 10 ng/mL.[1,2,9,10]

The most recent guidelines from the Food and Nutrition Board of the Institute of Medicine,published in 1997

(Table 1), suggest a daily minimum vitamin D intake of 200 International Units

(5 mcg) for infants, children, and adults up to 50 years of age to achieve serum 25 (OH)D levels

20 ng/mL and prevent bone disease. The recommended daily intake increases to 400

International Units (10 mcg) for adults 51 to 70 years of age and 600 International Units (15

mcg) for adults over 71 years of age.[11-14]

.However a study conducted by Holick M.F suggests

that if mothers are pregnant or lactating, they need more vitamin D for themselves and their

fetus/infant. To maintain the recommended serum 25(OH) D levels of above 30 ng/mL, a

pregnant or lactating woman requires 1000 to 2000 IU of vitamin D3 per day.This is especially

important in women living in higher latitudes during the fall and winter months, as they do not

get adequate sun exposure [21].Infants who are breastfeeding without supplementation or with

inadequate sun exposure are recommended to receive 400 to 1000 IU of vitamin D3 per day[10, 21]

Indications of Vitamin D and calcium supplements based on evidence based medicine have been

mentioned in table 5 and specific Forms of Vitamin D and Analogs of Calcitriol have been

mentioned in tables 3 and 4 respectively.

Illnesses that are associated with vitamin D deficiency in adults include autoimmune diseases

(such as rheumatoid arthritis [RA], diabetes, inflammatory bowel syndromes, and multiple

sclerosis [MS]), Hyperparathyroidism, low bone density, cardiovascular disease, and cancer[1, 10,

and 15]

The National Osteoporosis Foundation recommends that health professionals advise their

patients to consume adequate amounts of calcium (at least 1,200 mg/day, including supplements

if necessary). Studies also have concluded that 1,500 mg/day or more is recommended for

postmenopausal women not on estrogen therapy.[16-18].The most recent guidelines from the Food


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and Nutrition Board of the Institute of Medicine, published in 1997 have been mentioned in

Table 2

Among various calcium salts, calcium carbonate is the most widely used supplement, mainly

because it contains high elemental calcium content per unit weight. Other salts that are

commonly used as supplement includes calcium lactate, calcium gluconate, calcium citrate,

calcium phosphate and powdered oyster shell calcium. These calcium salts differ widely in their

solubility in water. [22] A study conducted by Naoko Tsugawa et al on the bioavailability of

calcium from calcium carbonate, calcium lactate and powdered oyster shell calcium in Vitamin

D deficient or replete rats showed that the difference in bioavailability were small and not

statistically significant thus concluding that calcium is utilized to the same extent from these

preparations.[23]

When vitamin D levels are deficient, dietary calcium is not absorbed adequately. This deficiency

disrupts phosphorus and calcium homeostasis, as well as bone mineralization. Therefore there is

a homeostasis maintained between Vitamin D and Calcium.

In our present study, the aim was to study and analyze the prescription pattern of Vitamin D and

calcium by the practicing physicians in a tertiary care teaching rural hospital, in order to

understand the rationality behind the use of the above preparations. It also aims at comparing the

costs of various preparations of Vitamin D and/or calcium in hospital pharmacy and also in a

typical drug index and to conduct a survey amongst physicians through a questionnaire regarding

rational use of Vitamin D and Calcium


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Table 1: Adequate Intakes (AIs) for Vitamin D[19]

Age Males Females Pregnancy Lactation

0-12 months5 mcg

(200 IU)

5 mcg

(200 IU)

1-13 years5 mcg

(200 IU)

5 mcg

(200 IU)

14-18 years5 mcg

(200 IU)

5 mcg

(200 IU)

5 mcg

(200 IU)

5 mcg

(200 IU)

19-50 years5 mcg

(200 IU)

5 mcg

(200 IU)

5 mcg

(200 IU)

5 mcg

(200 IU)

51-70 years 10 mcg(400 IU)

10 mcg(400 IU)

71+ years15 mcg

(600 IU)

15 mcg

(600 IU)

Table 2: Adequate Intakes (AIs) for Calcium[20]

Age Male Female Pregnant Lactating

0-6 months 210 mg 210 mg

7-12 months 270 mg 270 mg

1-3 years 500 mg 500 mg

4-8 years 800 mg 800 mg

9-13 years 1,300 mg 1,300 mg

14-18 years 1,300 mg 1,300 mg 1,300 mg 1,300 mg

19-50 years 1,000 mg 1,000 mg 1,000 mg 1,000 mg

50+ years 1,200 mg 1,200 mg


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Table 3

Specific Forms Of Vitamin D Property Indications Dose

Doxercalciferol (1-

hydroxyvitamin D2

Prodrug. Secondaryhyperparathyroidism

10 mg three times

per week (oral orintravenous

Dihydrotachysterol(DHT) A reduced form ofvitamin D2.

DHT is converted inthe liver to its active

form, 25-

hydroxydihydrotachysterol.

DHT is less than 1% asactive as calcitriol inantirachitic assays but

is much more effective

in mobilizing bonemineral at high doses

To maintain plasma

Ca2+ in

hypoparathyroidism

Oral

administration in

doses ranging

from 0.2 to 1mg/day (average

0.6 mg/day).

1-Hydroxycholecalciferol (1-OHD3, alphacalcidol)

A synthetic vitamin D3derivative that isalready hydroxylated in

the 1 position and is

rapidly hydroxylatedby 25-hydroxylase to

form 1,25-(OH)2D3

It is equal to calcitriolin assays for

stimulation of intestinal

absorption of Ca2+

and

bone mineralizationand does not require

renal activation.

To treat renalosteodystrophy .

Ergocalciferol (calciferol) Pure vitamin D2. It isavailable foradministration.Ergocalciferol is

indicated for the

typically in doses of

Prevention of

vitamin D deficiencyand the treatment offamilial

hypophosphatemia,

hypoparathyroidism,

and vitamin D-resistant rickets type

II,

50,000 to 200,000

units/day inconjunction withcalcium

supplements. (oral,

intramuscular, or

intravenous)


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Table 4

Analogs of Calcitriol Property Indications Dose

1. Calcipotriol(calcipotriene)

A synthetic derivativeof calcitriol.

Calcipotriol hascomparable affinity

with calcitriol for thevitamin D receptor,

but it is less than 1%

as active as calcitriol

in regulating calciummetabolism.

This reduced calcemicactivity largely

reflects the

pharmacokinetics ofcalcipotriol

[24

Treatment forpsoriasis, although its

mode of action is notknown

Topical

1. Paricalcitol (1,25-dihydroxy-19-

norvitamin D2

A synthetic calcitriolderivative that lacks

the exocyclic C19 andhas a vitamin D2

rather than vitamin D3

side chain.

It reduces serum PTHlevels without

producing

hypercalcemia oraltering serum

phosphorus [25].

Treatment of

secondary

hyperparathyroidism inpatients with chronic

renal failure.

Intravenous

2. 22-Oxacalcitriol(1,25-dihydroxy-22-

oxavitamin D3,

OCT, maxicalcitol)

Differs from calcitriolonly in the

substitution of C-22

with an oxygen atom.

Oxacalcitriol has alow affinity for

vitamin D-bindingprotein; as a result,

more of the drugcirculates in the free

(unbound) form,allowing it to be

metabolized more

rapidly than calcitriol

with a consequentshorter half-life. [26]

It is a useful compound

in patients with

overproduction of PTH

in chronic renal failureor even with primary

hyperparathyroidism[26]


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Table 5

Indications of Vitamin D on evidence based

medicine(27)

Indications of Calcium preparations on

evidence based medicine(27)

1. Prophylaxis and cure of nutritional rickets2. Treatment of metabolic rickets and

osteomalacia, particularly in the setting of

chronic renal failure3. Renal Osteodystrophy due to chronic

kidney disease

4. Treatment of hypoparathyroidism5. Prevention and treatment of osteoporosis6. Treatment of hypophosphatemia

associated with Fanconi syndrome

7. Psoriasis

1. Treatment of osteoporosis2. Vitamin D deficiency rickets with Vitamin

D deficiency

3. Osteomalacia patients who are prescribedVitamin D

4. Chronic kidney disease as phosphatebinders


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Material and Methodology

The study was prospective, non interventional, and comparative in nature. Approval from the

institutional ethics committee was obtained and all the information with regard to identity of

patients and physicians was strictly kept confidential

The study was based on the following three components:I. Preparation analysis:

Analysis of various preparations containing Vitamin D or/and calcium available in Indian

market was performed with the help of an Indian drug index, Drug today July-September

2009 issue for the following aspects

Evaluation of percentage of preparations containing both vitamin D andcalcium supplements

Type of salts available Cost analysis of different salts available and variations within the same

salt group

Amount & indications of the preparations

II. Prescription analysis:It was conducted by randomly selecting 100 prescriptions containing vitamin D or/and

calcium supplements from 4 departments- Medicine, Orthopedics, Obstetrics &

gynecology and Pediatrics from the hospital pharmacy. The prescriptions were analyzed

for rationality of the conditions mentioned based on standard guidelines for indications,

dose, frequency, duration of treatment and cost of treatment

III. Questionnaire analysis:A structured and pretested questionnaire was devised to collect information from

physicians at various levels of work and experience from departments of medicine,

pediatrics, orthopedics, obstetrics and gynecology and analyzed for:

Rationality of conditions for which prescribed Prescribing Behavior of various preparations of Vitamin D & Calcium for

type, dose, frequency, duration of treatment

Knowledge & Attitude by framing questions regarding use of Vitamin D orCalcium or both in various conditions & check knowledge about facts in the

form of True/false


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The inclusion and exclusion criteria for selection of prescriptions and physicians are as follows:

INCLUSION CRITERIA

I. For prescriptions:1. Prescriptions of all the departments prescribing Vitamin D or/and calcium supplements2. Prescriptions from patients of either sex and all age groups.

II. For physicians:1. Physicians working in department of Medicine, Pediatrics, Orthopedics and Obstetrics

and Gynecology

2. Physicians working at various levels i.e. Professors, Associate Professors, assistantProfessors, Tutors, senior Residents.

3. Physicians agreeing to participate and willing to sign the informed consent form.

EXCLUSION CRITERIA

I. For prescriptions:1. Prescriptions not containing Vitamin D and/or Calcium preparations

II. For physicians:1. Physicians from departments other than Medicine, Pediatrics, Orthopedics and Obstetrics

and Gynecology.

2. Physicians not willing to participate or sign the ICF

Statistical Methods

Data was analyzed by using Chi-square test (2). P-value 0.05 was considered as significant.


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Results

I. Preparation analysis Total 656 multivitamins were analyzed containing various vitamin preparations out of

which 368 (56.09%) were found to be without vitamin D or Calcium and the

remaining 288 (43.91%) were found to have either calcium supplement only (118,

17.9%) or vitamin D only (82, 12.5%) or in combination (88, 13.4%). (Figure1)

Total 595 preparations containing vitamin D and Calcium were analyzed, out ofwhich 538 (90.42%) preparations were in combination and only 57 (9.58%)

preparations contained vitamin D or Calcium as a single component.(Figure2)

Out of the above mentioned 538 (90.42%) preparations containing vitamin D andCalcium in combination, 285 (48%) contained combination of vitamin D3 with

Calcium carbonate and 115 (20%) contained combination of Calcium carbonate with

Alfacalcidol and 138 (22%) contained combination of other vitamin D and Calcium

salts.(Figure2)

Cost of Organic Calcium Carbonate (chiefly from Oyster shell) was found to be 9times (3.26/0.35) expensive than Inorganic Calcium carbonate for the same dosage.

Figure1


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Figure 2

II. Questionnaire analysis Questionnaire was taken by total 37 doctors belonging to the above mentioned 4

departments of which 13 were Senior doctors ( Assistant professor, Associate

professor, Professor) and 24 were Junior doctors ( Senior residents)

Total 45 conditions were mentioned by the doctors for which vitamin D or/ andcalcium was indicated, out of which only 23 ( 51% ) conditions mentioned werefound to be rational according to standard textbook guidelines

The most common form of Vitamin D prescribed by them was Vitamin D3 in a doseof 250 IU/tablet

The most common calcium salt prescribed by them was Calcium Carbonate in a doseof 500mg elemental calcium

The most common frequency for the above medications was twice a day for aduration of 1 month.

16 (63%) junior doctors and 9 (69%) senior doctors believed that organic calcium(oyster shell) has higher bioavailability than inorganic calcium (2 = 0.343 , p>0.05)

14 (58%) junior doctors and 9 (70%) senior doctors believed that all pregnant womenand lactating mothers should receive vitamin D or/and calcium supplements (2 =

6.07 , p


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III. Prescription analysisDepartment Prescriptions Male Female

Orthopedics 39 21 18

Medicine 36 11 25

Obstetrics and gynecology 14 - 14

Pediatrics 11 7 4

Total 100 39 61

Overall female to Male ratio observed was 1.56:1 Rationality based on appropriateness of selection of formulations have been shown in the

table below

Appropriateness of selection of formulations

Rational Irrational

Vitamin D 21(21%) 79(79%)

Calcium supplements 38(38%) 62(62%)

Out of the above mentioned 21 rational vitamin D preparations, only 19% (4/21) werefound to be in adequate dose

Out of the above mentioned 38 rational calcium preparations, only 24% (9/38) werefound to be in adequate dose.

Most common form of vitamin D prescribed was Vitamin D3 (100%) Most common calcium salt prescribed was Calcium Carbonate (93%) Most common frequency and duration of treatment was twice a day for 1 month Most common cost of treatment with the brand used = Rs 131- 153/month


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Discussion and conclusion

This study has shown that:

1. Almost half of the multivitamin preparations contain Vitamin D or/and Calcium invarying doses. This may not be consistent with the indications of Vitamin D or/and

calcium

2. Almost 90% of the formulations containing Vitamin D or/and calcium are fixed dosecombinations (FDCs).All these FDCs have no valid bases as no such FDCs mentioned in

the Model List of Essential Medicine (WHO) 2010.(28)

3. Formulations containing organic calcium were found to be 9 times costlier thanformulations containing inorganic calcium, despite the fact that there is no greater

bioavailability from organic source(23)

65% of the doctors in a tertiary care teaching hospital believed otherwise. This isreflected in the practice where in 93% of prescriptions contained organic (Oyster)calcium. This could be a result of inadequate training and aggressive marketing

practice.

4. Despite the fact that there is no specific role of Vitamin D or/and calciumsupplementation in pregnant woman, lactating mothers and post-menopausal women (12,

20)all 14 (100%) prescriptions from obstetrics and gynecology department had these

formulations for the same condition

Though the choice of rational formulations was in 21% and 38% with regard toVitamin D and calcium, it effectively boiled down to 4% and 9% respectively,when adequacy of dose was considered. This implies that selecting just a rational

medicine for the indication is not enough. The route of administration, dose &

frequency of administration and the duration of therapy should be appropriate for

rational management.


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