Effect of Pradaxa vs Warfarin on Bone Mass and Bone Turnover Markers

1.0 Hypothesis: The direct thrombin inhibitor Pradaxa positively affects bone turnover
markers and increases bone mineral density in women and men at risk for osteoporosis.

2.0 Goal: The goal of this study is to establish if the direct thrombin inhibitor Pradaxa
positively affects bone turnover markers and increases bone mineral density in women and men
at risk for osteoporosis.

3.0 Specific Aims.

3.1 To determine the effect of Pradaxa on bone mineral density in patients after 6 and 12
months of daily use.

3.2 To determine the effect of the direct thrombin inhibitor Pradaxa on bone turnover
markers for osteoclastic resorption (measured as serum levels of C-terminal peptide, and
N-telopeptide) and osteoblastic formation (measured as serum levels of bone-specific
alkaline phosphatase, osteocalcin and P1NP) in subjects after 6 and 12 months of daily use.

3.3 To evaluate any correlation among the hemoclot, thrombin inhibitor test, changes in
markers of bone turnover and changes in bone mineral density in patients on Pradaxa.

3.4 To determine the effect of Pradaxa on change in serum levels of receptor activator of NF
B-ligand (RANKL), osteoprotegerin (OPG), RANKL/OPG ratio, inflammatory markers (IL-1b, IL-6,
TNF-alpha and FGF-23) and inhibitors of Wnt/beta-catenin signaling pathway including
sclerostin and DKK1 at baseline, 6 and 12 months, to understand the mechanisms for the
effect of Pradaxa on bone.

4.0 Study design and procedures.

4.1 Study Design:

This will be a prospective, Phase IV age-matched cohort study in men and women who are being
started on long-term treatment with Pradaxa for nonvalvular atrial fibrillation. This is a
proof of concept study evaluating the effect of Pradaxa, a direct thrombin inhibitor on bone
density and bone turnover markers in comparison to warfarin.

4.2 Subject Population:

The investigators will be recruiting patients with nonvalvular atrial fibrillation who are
being prescribed Pradaxa by their cardiologists or primary care providers for long-term
anticoagulant treatment for participation in the study. The patients taking Pradaxa will be
the study group, and will be compared to an age-matched cohort of men and women with
nonvalvular atrial fibrillation who are being started on long-term warfarin by their
cardiologists or primary care providers (control group). The investigators will be
evaluating 20 men and 20 women in the Pradaxa cohort and another age-matched 20 men and 20
women in the warfarin cohort (Pradaxa cohort: N = 40, 20 men, 20 women; Warfarin cohort: N =
40, 20 men, 20 women). The two groups will be determined based on treatment assigned to them
by their cardiologists or primary care providers. As age can influence the risk for
osteoporosis, the warfarin group will be age-matched to the Pradaxa group for optimal
comparison. This will be achieved by offering participation to patients taking warfarin who
are similar in age to the patients being recruited for the Pradaxa group. As women are more
likely to develop osteoporosis and the effects of Pradaxa may be gender-based as a result of
differences in the levels of sex hormones, the investigators are evaluating a cohort of men
and women in this pilot study for comparison.

The investigators expect to see an older cohort of subjects with atrial fibrillation, who
are also likely to have an increased risk of osteoporosis.

Inclusion Criteria:

1. Age 50 and above, male and female starting on Pradaxa or Warfarin for nonvalvular
atrial fibrillation

2. Able to ambulate independently and travel to UConn Health in Farmington CT-

Exclusion Criteria:

1. Prior known history of osteoporosis

2. Chronic kidney disease with creatinine clearance less than 30

3. Serum 25 hydroxyvitamin D level less than 10

4. Ongoing treatment with medications that interfere with bone metabolism such as
steroids, bisphosonates, denosumab, estrogen, SERMS

5. Hypercalcemia, a history of Paget's disease, a history of multiple myeloma, or a
history of monoclonal gammopathy of uncertain significance -