Tumor Necrosis Factor Decreases Vitamin D Dependant Calcium Absorption
Condition: Rheumatoid Arthritis; Crohn's Disease
MeSH terms: Crohn Disease; Necrosis
Study type: Interventional

Summary: 
      This study is a pilot study to determine whether patients with TNFα excess have decreased
      calcium absorption in response to calcitriol (1,25-dihydroxyvitamin D, the active form of
      vitamin D) compared to normal controls. This initial pilot study is being done to determine
      if it is feasible to conduct a study where TNFα could be blocked (e.g., by anti-TNFα therapy
      such as Enbrel® or Remicade®) to improve vitamin D dependant calcium absorption and thus bone
      health.
    

Detailed description: 
      Vitamin D is important for the maintenance of normal calcium homeostasis by improving the
      efficacy of calcium absorption from the small intestine. The efficacy of calcium absorption
      is decreased with aging, menopause, and other inflammatory states. Subjects who have low
      intestinal absorption of calcium are at risk for developing osteoporosis and fractures. Early
      data suggests that patients with rheumatoid arthritis (RA) and Crohn's disease appear to have
      decreased calcium absorption. Patients with RA and Crohn's disease have elevated levels of
      TNFα in local tissues and systemically which may be causing resistance to vitamin D dependant
      calcium absorption.

      Recently a new vitamin D dependant calcium channel important for calcium absorption has been
      discovered in the small intestine called Transient Receptor Potential Vallinoid type 6
      (TRPV6). We have some pre-clinical data in rats to suggest that TNFα has a role in inhibiting
      the expression of this protein by decreasing the induction of this protein in response to
      vitamin D treatment.

      HYPOTHESIS:

      Subjects with disease conditions that result in elevated TNFα have vitamin D resistance and
      inability to increase calcium absorption with increasing concentrations of calcitriol.

      STUDY DESIGN:

      Subjects: The study will be conducted at the Emory GCRC/Emory Clinic and VA clinical research
      center. Study participants will be recruited from the Atlanta Veterans Administration Medical
      Center (VAMC) and Emory Clinics for participation in the study according to the following
      inclusion and exclusion criteria

      Inclusion: Males, age 18 to 50, history of Crohn's disease or Rheumatoid Arthritis (cases) or
      healthy individuals (controls)

      Exclusion: Subjects already taking activated vitamin D medications such as calcitriol,
      Zemplar®, Hectoral®, vitamin D deficiency defined as 25(OH)D ≤ 20 ng/ml, post-menopausal
      women (absence of menses for greater than 6 months by history or FSH level >20), history of
      nephrolithiasis, history of hypercalcemia or hypercalciuria, short bowel disease,
      glucocorticoid use, use of osteoporosis medication (bisphosphonate, calcitonin or
      teriparatide), chronic kidney disease (calculated GFR <60 ml/min/1.73 m2), history of
      hyperparathyroidism (PTH greater than upper limit of normal) or hypoparathyroidism (PTH below
      lower limit of normal)

      Procedures:

      Screening Phase: Case subjects will be identified from Rheumatology and Gastroenterology
      clinics from the VA or Emory Clinic. The subject's doctors will give the patient a brochure
      of the study with the study investigator's name and phone number to contact. There will also
      be advertisements in the Rheumatology and Gastroenterology clinics to recruit subjects for
      the study. Control subjects will be identified by postings at the VA hospital or at Emory
      Clinic in designated areas for research postings.

      The subject will initiate contact with the study personnel by calling the number on the
      advertisement or brochure. The study investigator will pre-screen the subject on the phone to
      see if the subject is eligible for entry into the study. If the subject remains eligible, the
      subject will be invited to the VA clinical research center or Emory GCRC/Emory Clinic for
      informed consent.

      Screening Visit: The study investigator will review the inclusion and exclusion criteria with
      each subject. If the subject agrees to participate in the study, the subject will sign the
      informed consent and undergo baseline laboratory investigations for total calcium,
      parathyroid hormone (PTH), 25-hydroxyvitamin D, comprehensive panel including renal function,
      24-hour urine collection for calcium and creatinine clearance. Subjects will be counseled to
      take no more than 600 mg of calcium daily and no more than 400 IU a day of vitamin D. The
      subjects will be instructed on how to complete a three day food diary for future visits.

      They will be given a schedule to return for the following visits.

      Visit #1 (baseline fractional absorption of calcium (FCA)) Subjects will return to the
      clinical research center in a fasting state for a baseline FCA test (see specific methods in
      the following section). Subjects will return their three day food diary record. Subjects will
      also have blood drawn for comprehensive panel including calcium and renal function,
      1,25-dihydroxyvitamin D, PTH level and serum TNFα. The subjects will be given calcitriol 0.25
      mcg PO BID to be taken for 7 days.

      Visit #2 (FCA on low dose calcitrol, 0.25 mcg PO BID) Subjects will take their morning dose
      of calcitriol 8 am on the day of visit #2. Subjects will come to the clinic in a fasting
      state. They will return their 3 day food diary records. A repeat FCA will be performed.
      Subjects will also have blood drawn for comprehensive panel including calcium and renal
      function, 1,25-dihydroxyvitamin D, PTH level and serum TNFα. After the test is completed, the
      subjects will be given calcitriol 0.50 mcg PO BID to be taken for 7 days. They will be
      scheduled to return to the clinical research center within 20 days after a minimum 7 day
      washout period.

      Visit #3 (FCA on high dose calcitriol, 0.50 mcg PO BID) Subjects will take their morning dose
      of calcitriol at 8 am on the day of visit #3. Subjects will come to the clinic in a fasting
      state. They will return their 3 day food diary records. A repeat FCA will be performed.
      Subjects will also have blood drawn for comprehensive panel including calcium and renal
      function, 1,25-dihydroxyvitamin D, PTH level and serum TNFα.

      Fractional absorption of calcium (FCA) procedure Subjects will come to the clinic after an
      overnight fast. After voiding the fasting urine, a 24 hour urine collection will begin. Each
      subject will receive a standard breakfast (see FCA diet section) which will contain
      approximately 211 mg of calcium and 45 IU of vitamin D. Oral 43Ca will be administered after
      the patient has drunk the milk. 1.9 ml will be drawn from a sterile 43Ca (calcium chloride)
      vial with a syringe and will be injected in 4 ounces of distilled water. The subject will
      drink the glass of water. The glass will be rinsed twice with 4 ounces of distilled water and
      the subject will drink each rinse.

      2.7 ml of 42Ca will be drawn from a sterile 42Ca (calcium chloride) vial with a sterile
      hypodermic syringe. The solution will be injected into the patient intravenously with an IV
      catheter and flushed with 5 ml of normal saline. The intravenous calcium will be infused
      within 30 minutes of ingestion of the oral calcium.

      The subject will be discharged from the clinical research center and will continue with their
      24 hour urine collection. The following morning, the subject will return the 24 hour urine
      collection to the research clinic. The subject will be advised to not eat for at least 4
      hours after the breakfast meal.
    

Intervention name(s): calcitriol
Intervention type(s): Drug
Intervention description(s): 0.25 mcg PO BID for 1 week for low dose then 0.25 mcg PO BID for high dose
Intervention MeSH terms: Calcitriol
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Calcium absorption; Vitamin D