Abstract |
The use of anticoagulants is crucial for patients recovering from orthopedic surgery since with
this prophylactic treatment, thromboembolism can be prevented. In order to do so,
physicians, prescribe their patients different classes of anticoagulants. Initially, heparin was
the first drug prescribed, but its correlation to bone fractures and other side effects, led on
developing new drugs, with Low Molecular Weight Heparins (LMWHs) being discovered.
Another class, also used in effectively treating thromboembolism is Vitamin K antagonists,
but they are also linked to bone malfunction among others. Direct Oral Anticoagulants
(DOACs) is the newest class, and is considered patient friendly, since its administration is oral
and does not require intensive monitoring. Unfortunately, DOACs are merely studied
regarding bone malfunctions, with the relevant studies showing contradicting results and
being of restricted extent.
In this study, there is an attempt to investigate the effect of DOACs on bone metabolism, by
studying how DOACs affect bone differentiation of mouse derived pre-osteoblasts MC3T3-E1.
Five drugs were chosen for assessment depending on their class, Fondaparinux, a synthetic
pentasaccharide, Rivaroxaban and Apixaban, direct inhibitors of factor Xa, Dabigatran
etexilate, a direct thrombin inhibitor and Enoxaparin, a LMWH. For the exported results to be
comparable, the same drug concentrations should be used, and for this reason, the
administered dosage of the drugs was used to estimate the corresponding concentrations,
ending up in 10-7, 10-6 and 10-5 M. The parameters chosen to be investigated were 1. cell
viability, 2. enzymatic Alkaline Phosphatase (ALP) Activity, 3. Calcium mineralization, 4. total
collagen secretion and 5. relative expression levels of SPP1 (osteopontin), SPARC
(osteonectin) and BGLAP (osteocalcin) genes.
According to the data collected, the drugs do not affect the cell viability and Calcium
mineralization in the tested concentrations (10-7, 10-6, 10-5 M), and no significant variation
was found in the expression levels of SPP1 and BGLAP. On the contrary, ALP activity, total
collagen secretion and expression levels of SPARC, were decreased compared to the control
group indicating that all the drugs demonstrate an inhibitory effect on bone differentiation.
Moreover, comparing the effect of the drugs, it becomes clear that Fondaparinux is the less
affecting drug, with the milder decrease in ALP activity and collagen secretion and the most
affecting is Dabigatran etexilate. Thought-provoking are the results of Apixaban and
Rivaroxaban, two drugs that are both direct factor Xa inhibitors and, thus, were expected to
influence bone formation in a similar manner, but Apixaban affects the most the ALP activity,
and Rivaroxaban the secreted collagen.
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