Cholecalciferol Supplementation, Muscle Strength
Cholecalciferol Supplementation, Muscle Strength
Hypovitaminosis D is common in Asian Indians despite plenty of sunshine and relates to their
 skin pigmentation and poor sunshine exposure. Serum 25(OH)D levels are <20 ng /ml in up to
 90% of them and therefore, based on the modern cut off, majority of apparently healthy normal
 Asian Indians would be classified as vitamin D deficient. Though, several investigators have
 highlighted the paradox of hypovitaminosis D in sunny Indian environment, there are only
 limited studies which have assessed its functional significance. To date, the significance of
 low serum 25(OH)D in them have been analyzed in terms of its inverse relationship with serum
 parathyroid hormone levels and variable association with reduced bone mineral content at hip
 and spine on DXA. Recently we have shown impairment in the absorption of intestinal calcium
 in 25(OH)D and its reversal after eight weeks of cholecalciferol supplementation. Present
 study is being taken to further understand the functional significance of 25(OH)D in terms of
 its effect on Skeletal muscle strength including its energy metabolism, bone mineral
 homeostasis and Th1/Th2 cytokines expression in Asian Indians with chronic biochemical
 hypovitaminosis D
Vitamin D is an essential nutrient that plays an important role in calcium metabolism and
 bone health. In recent years, biomarkers like PTH, calcium absorption have been used to
 define relevant biological indices of vitamin D nutritional status.

 Prevalence of 25(OH)D in Asian Indians Several studies from India have shown wide prevalence
 of vitamin D deficiency (VDD) in India, Goswami et al studied serum 25 (OH)D levels and its
 functional significance in apparently healthy subjects residing in Delhi. In this study three
 groups of subjects (soldiers, depigmented person and physicians and nurses) were studied in
 winter. Other three groups namely pregnant women, newborns and physicians and nurses were
 studied in summer. All the groups except one with maximum sunlight exposure (soldiers) had
 subnormal concentration of serum 25(OH) D levels. Vitamin D deficient groups tended to have
 an imbalance in bone mineral homeostasis when exposed to winter and low dietary calcium and
 high dietary phytate, with significantly low serum calcium and elevated PTH.On the basis of
 the studies related to the intestinal calcium absorption, inverse relation with serum iPTH
 concentration and protection from fracture risk, a recent consensus has suggested that an
 ideal health based normal cutoff of circulating serum 25(OH) D would at least be 32 ng/mL.
 Interestingly, using the above consensus, recent studies conducted at AIIMS, by Goswami et al
 , have shown that 94.3% of the apparently healthy northern Indian subjects residing in Delhi
 were vitamin D deficient (AJCN 2006, BJN 2008).

 Functional Significance of 25(OH)D deficiency Though there have several studies highlighting
 widespread prevalence of 25(OH)D in Asian Indians, there is paucity of data on its functional
 significance. Relevant studies assessing functional significance of VDD in Asian Indians are
 summarized below (Am J Clin Nutr 2000).

 A) Effects on Serum PTH levels Goswami et al while reporting low serum 25(OH) D
 concentrations in healthy subjects in Delhi, showed a higher serum PTH levels & significant
 inverse relation between serum 25(OH) D and PTH levels ( r = -0.6303, p < 0.001) in all the
 three groups (soldiers, physicians & nurses, depigmented persons) studied in winter (Am J
 Clin Nutr 2006) B) Effects on BMD Recently,we have analyzed relationship between BMD and
 serum 25(OH) D in 105 apparently healthy Asian Indian. The cohort of 105 subjects was split
 into 2 groups at a serum 25(OH) D cutoff of 9.0 ng/mL. The mean serum iPTH was significantly
 higher in the group 1 (<9.0 ng/ml)than in the group 2 subjects (53.1±31.3 and 39.3±17.5
 pg/mL, respectively; P=0.012).The mean BMD values of the total hip, including femoral neck,
 trochanter, and intertrochanter, were significantly (P = 0.001) lower in group 1 than in
 group 2.

 C) Effects on intestinal calcium absorption Effect of VDD on intestinal calcium absorption in
 Asian Indians with chronic hypovitaminosis D and its change after cholecalciferol
 supplementation was studied recently at our Department of Endocrinology and Metabolism. Study
 subjects were 29 apparently healthy volunteers [17 M, 12 F, mean (SD) age = 28.4 ± 6.4 year]
 with low serum 25(OH)D levels [mean (SD) = 7.6 ± 4.8 ng/ml]. Intestinal calcium absorption
 was assessed by 'calcium load test' (PAK test) (10) using 1 gm of oral elemental calcium load
 before and after (n = 26) supplementation with oral cholecalciferol (60,000 IU/week for eight
 weeks). This study showed that the vitamin D Deficiency is physiologically relevant in terms
 of intestinal calcium absorption in Asian Indians.

 D) Effects on physical performance and related skeletal muscle strength Zamboni et al showed
 a significant association between serum 25(OH)D levels and muscle strength and physical
 performance as noticed in 6 - minute walk test in elderly women. However to date there has
 been no study which has systematically assessed role of cholecalciferol supplementation in
 improving muscle strength a randomized placebo controlled trial in apparently healthy who
 have chronic hypovitaminosis D.

 The present study would include 40 apparently healthy volunteers (medical and paramedical
 staff).

 Complete evaluation of daily dietary intake including calcium and phytic acid will be done by
 semiquantitative of frequency questionnaire and 24 - h recall method using published data of
 nutritive value of Indian food. Subjects will be enquired about their average duration of sun
 exposure between 10 a.m. to 4 p.m. and average body surface area exposed.

 Baseline evaluation (Before vitamin D supplementation) Serum total calcium, inorganic
 phosphorus, alkaline phosphatase, intact PTH and 25(OH) D assays. At baseline, assessment of
 bone density at hip, spine and forearm would also be performed by DEXA

 At baseline isokinetic gastrosoleus strength testing will be done using a computerized
 dynamometer (Biodex Medical System) in the Department of Physical Medicine and Rehabilitation
 under the guidance of Professor U Singh, Head, Department of Department of Physical Medicine
 & Rehabilitation, AIIMS.. Subjects will perform three maximal planter flexion repetitions
 with right lower limb at 180 degree/sec. The peak strength will be recorded in Newton.
 Handgrip strength will be measured in right hand by hand dynamometer. The average of two
 measurement of grip strength will be used for analysis (in kg).

 The respiratory muscle strength testing will be done using a digital instrument (Micromedical
 respiratory pressure meter) and measuring the maximal inspiratory pressure & maximal
 expiratory pressure in the Department of Medicine under the guidance of Dr Randeep Guleria.

 The physical performance will be tested by performing 6 - minute walk test using standard
 protocol and results will be interpreted in terms of 6 minute walk distance in meters and
 degree of shortness of breath using modified Borg dyspnea scale.

 31P MRI spectroscopy would be performed in all the of subjects for muscle energy parameters,
 in the department of Nuclear Magnetic Resonance under the guidance of Professor NR Jagnathan.

 The mRNA expression Th1 and Th2 cytokines would be assessed in the PBMC drawn from 5 ml of
 the peripheral blood using the real time PCR.

 Vitamin D supplementation

 All the 40 subjects will be randomized in 1:1 ratio (Active: placebo) into treatment group
 and placebo group in 2:1 ratio in a double blind manner. Random code would be generated by a
 investigator, who will not be involved in distribution of medicines and assessment of the
 muscle strength Active drug would be calcium (two tablets of calcium carbonate each
 containing 500 mg of elemental calcium/day, and 60,000 IU of cholecalciferol/week obtained
 from the commercial source. The inactive drug would be lactose containing identical placebo
 obtained from the same source. All study subjects will be provided with packets containing
 four sachets of cholecalciferol (each containing 60000 IU vitamin D3; Cadila Pharmaceutical,
 India) /placebo; and sixty tablets of calcium carbonate (500mg elemental calcium & 250 IU
 vitamin D3; Elder Pharmaceutical, India)/placebo. First dose will be supervised. Subjects
 will be counseled for daily intake of two tablets of calcium carbonate and weekly intake of a
 cholecalciferol sachet and follow up at completion of 4 weeks. Similar packets will be given
 after 4 weeks of follow up. Drug compliance will be assessed by counting the empty sachets.
 After eight week subjects will be provided daily two tablets of calcium carbonate containing
 500 mg elemental calcium each and 250IU of Vitamin D3.

 Assessment at 8 weeks, 6 months, and 1 year Repeat evaluation at 8 weeks and six months and
 one year would include serum intact PTH & 25(OH) D levels estimation, skeletal muscle
 strength testing, respiratory muscle strength testing and 6 minute walk test 31P MRS and
 Th1/Th2 analysis

 Safety of Proposed Interventions Cholecalciferol dose of 60000 IU/week × 8 weeks is
 considered safe to be used in healthy subjects, as shown in our recent study. Also in another
 study done at Department of Endocrinology and Metabolism, AIIMS as a DM dissertation work by
 Dr. Ajay Gupta, the same dosage of vitamin D was supplemented to a cohort of 29 apparently
 healthy individuals. None of the study subject developed hypercalcemia or hypercalciuria.
 Study by A Malabanan et al (Lancet 1998) also showed that 50000 IU replacement of vitamin for
 8 weeks effectively normalize 25(OH)D levels, and corrects secondary hyperparathyroidism with
 no adverse effects.
Inclusion Criteria:

 -  Age > 20 years

 -  Residence of Delhi

 -  Commitment for follow-up at 8 weeks, 6 months & 1 year.

 -  Consent for 8 weeks of supplementation

 Exclusion Criteria:

 -  Subjects taking drugs, which can affect bone mineral metabolism such as
 glucocorticoids, antitubercular, antiepileptics, levothyroxine, bisphosphonates

 -  Chronic renal or liver disorder

 -  Chronic diarrhea