Rivaroxaban significantly inhibits the stimulatory effects of bone-modulating hormones: In vitro study of primary female osteoblasts.
BACKGROUND
Anticoagulant therapy is a mainstay of treatment subsequent to major orthopedic surgeries. Evidence linking anticoagulant therapy, osteoporosis, and delayed fracture healing is not conclusive. We have previously reported that rivaroxaban significantly inhibited cell growth and energy metabolism in a human osteoblastic cell line. This study analyzed the response of primary female osteoblast cells to rivaroxaban in combination with various bone-modulating hormones.


METHODS
Bone samples were taken from both premenopausal (pre-Ob) and postmenopausal (post-Ob) women. Cells were isolated from each sample and cultured to sub-confluence. Each sample was then treated with Rivaroxaban (10 µg/ml) in combination with the following hormones or with the hormones alone for 24 hours: 30nM estradiol-17β (E2), 390nM estrogen receptor α (ERα) agonist PPT, 420nM estrogen receptor β (ERβ) agonist DPN, 50nM parathyroid hormone (PTH), and 1nM of vitamin D analog JKF.


RESULTS
No effects were observed after exposure to rivaroxaban alone. When pre-Ob and post-Ob cells were exposed to the bone-modulating hormones as a control experiment, DNA synthesis and creatine kinase (CK)-specific activity was significantly stimulated with a greater response in the pre-Ob cells. When the cells were exposed to rivaroxaban in combination with bone-modulating hormones, the increased DNA synthesis and CK-specific activity previously observed were completely attenuated.


CONCLUSIONS
Rivaroxaban significantly inhibited the stimulatory effects of bone-modulating hormones in both pre-Ob and post-Ob primary human cell lines. This finding may have clinical relevance for patients at high risk of osteoporosis managed with rivaroxaban or other factor Xa inhibitors.
a Institute of Endocrinology, Metabolism and Hypertension, Tel-Aviv Sourasky Medical Center and the Sackler Faculty of Medicine , Tel-Aviv University , Tel-Aviv , Israel.
Dalia
D
Somjen
b Division of Orthopedic Surgery, Tel-Aviv Sourasky Medical Center and the Sackler Faculty of Medicine , Tel-Aviv University , Tel-Aviv , Israel.
Zachary T
ZT
Sharfman
a Institute of Endocrinology, Metabolism and Hypertension, Tel-Aviv Sourasky Medical Center and the Sackler Faculty of Medicine , Tel-Aviv University , Tel-Aviv , Israel.
Sara
S
Katzburg
a Institute of Endocrinology, Metabolism and Hypertension, Tel-Aviv Sourasky Medical Center and the Sackler Faculty of Medicine , Tel-Aviv University , Tel-Aviv , Israel.
Orli
O
Sharon
b Division of Orthopedic Surgery, Tel-Aviv Sourasky Medical Center and the Sackler Faculty of Medicine , Tel-Aviv University , Tel-Aviv , Israel.
Eran
E
Maman
b Division of Orthopedic Surgery, Tel-Aviv Sourasky Medical Center and the Sackler Faculty of Medicine , Tel-Aviv University , Tel-Aviv , Israel.
Moshe
M
Salai
a Institute of Endocrinology, Metabolism and Hypertension, Tel-Aviv Sourasky Medical Center and the Sackler Faculty of Medicine , Tel-Aviv University , Tel-Aviv , Israel.
Naftali
N
Stern
b Division of Orthopedic Surgery, Tel-Aviv Sourasky Medical Center and the Sackler Faculty of Medicine , Tel-Aviv University , Tel-Aviv , Israel.
Oleg
O
Dolkart
D000328:Adult; D002478:Cells, Cultured; D004336:Drug Antagonism; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D036145:Ginsenosides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006801:Humans; D008875:Middle Aged; D009570:Nitriles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D017698:Postmenopause / Q000378:metabolism*; D017697:Premenopause / Q000378:metabolism*; D000069552:Rivaroxaban / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D012502:Sapogenins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011422:Propionates
D004958:Estradiol; D036145:Ginsenosides; D009570:Nitriles; D000069552:Rivaroxaban; D012502:Sapogenins; C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D011422:Propionates; C507965:ginsenoside 20S-protopanaxatriol
Calciotrophic hormones; cell proliferation; energy metabolism; estrogens; human female osteoblasts; rivaroxaban