Cholecalciferol Supplementation, Muscle Strength
Condition: Vitamin D Deficiency
MeSH terms: Vitamin D Deficiency
Study type: Interventional
Phase: Phase 1

Summary: 
      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
    

Detailed description: 
      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.
    

Intervention name(s): Cholecalciferol; Lactose placebo
Intervention type(s): Drug; Drug
Intervention description(s): Drug: Cholecalciferol 60,000 IU sachet and calcium carbonate Oral cholecalciferol (vitamin D)60,000 IU weekly along with daily oral dose of 1 gm calcium carbonate for first two months followed by 1 gm of elemental calcium in form of calcium carbonate daily cholecalciferol (vitamin D)60,000 IU per month for the next four months; Lactose placebo granules in identical sachet given weekly and two lactose tablets for first two months followed one sachet of placebo granules every month and two tablets of lactose containing placebo tablets taken daily for next four months
Other intervention name(s): Vitamin D; placebo granules and tablets
Intervention MeSH terms: Vitamin D; Cholecalciferol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Health Services Research
Keywords: 25(OH)D, muscle strength