Biological and clinical effects of abiraterone on anti-resorptive and anabolic activity in bone microenvironment

Abstract

// Michele Iuliani 1 ,* , Francesco Pantano 1 ,* , Consuelo Buttigliero 2 , Marco Fioramonti 1 , Valentina Bertaglia 2 , Bruno Vincenzi 1 , Alice Zoccoli 1 , Giulia Ribelli 1 , Marcello Tucci 2 , Francesca Vignani 2 , Alfredo Berruti 3 , Giorgio Vittorio Scagliotti 2 , Giuseppe Tonini 1 and Daniele Santini 1 1 Translational Oncology Laboratory, Medical Oncology, University Campus Bio-Medico of Rome, Rome, Italy 2 Department of Oncology, University of Turin, San Luigi Hospital, Orbassano, Turin, Italy 3 U.O. Oncologia Medica, Ospedali Civili di Brescia, Brescia, Italy * These authors have contributed equally to this work Correspondence to: Daniele Santini, email: // Keywords : abiraterone acetate, osteoclast, osteoblast, bone marker Received : February 06, 2015 Accepted : March 03, 2015 Published : March 30, 2015 Abstract Abiraterone acetate (ABI) is associated not only with a significant survival advantage in both chemotherapy-naive and -treated patients with metastatic castration-resistant prostate cancer (mCRPC), but also with a delay in time to development of Skeletal Related Events and in radiological skeletal progression. These bone benefits may be related to a direct effect on prostate cancer cells in bone or to a specific mechanism directed to bone microenvironment. To test this hypothesis we designed an in vitro study aimed to evaluate a potential direct effect of ABI on human primary osteoclasts/osteoblasts (OCLs/OBLs). We also assessed changes in bone turnover markers, serum carboxy-terminal collagen crosslinks (CTX) and alkaline phosphatase (ALP), in 49 mCRPC patients treated with ABI. Our results showed that non-cytotoxic doses of ABI have a statistically significant inhibitory effect on OCL differentiation and activity inducing a down-modulation of OCL marker genes TRAP, cathepsin K and metalloproteinase-9. Furthermore ABI promoted OBL differentiation and bone matrix deposition up-regulating OBL specific genes, ALP and osteocalcin. Finally, we observed a significant decrease of serum CTX values and an increase of ALP in ABI-treated patients. These findings suggest a novel biological mechanism of action of ABI consisting in a direct bone anabolic and anti-resorptive activity.