Tumor Necrosis Factor-α Induces Vitamin D Resistance in Small Intestinal Calcium Absorption
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.
Subjects with disease conditions that result in elevated TNFα have vitamin D resistance and
inability to increase calcium absorption with increasing concentrations of calcitriol.
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)
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
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
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.
Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Intestinal Absorption of Calcium
Vin Tangpricha, M.D. Ph.D.
United States: Federal Government
|Atlanta VAMC||Decatur, Georgia 30033|