Kyoto Pharmaceutical Industries, Ltd. KYOTO, Kyoto, Japan
Purpose: Osteoporosis is caused by an imbalance between bone formation and resorption in bone remodeling. As resorption inhibitors, oral and parenteral bisphosphonates have been used as therapy for osteoporosis patients. However, as osteogenetic drugs, only parenteral drugs such as parathyroid hormone and anti-sclerostin antibody are used. Thus, oral osteogenetic drugs with high efficacy and safety are desired. In the present study, we investigated the effects of orally administered 2-oxo-4-[4-(tetrahydropyran-4-yloxymethyl)phenyl]-2H-chromene-6-carboxamide (KY-054), which was discovered in our laboratories, on bone parameters in ovariectomized rats (OVX). Methods: Established mouse mesenchymal stem cells (MSCs) (ST2 cells) was cultured with and without KY-054 for 4 days, and then cellular alkaline phosphatase (ALP) activity, an osteoblast marker, was determined. OVX rats were orally treated with KY-054 (3 and 10 mg/kg/day) for 8 weeks, and femur bone parameters were measured using dual-energy X-ray absorptiometry (DEXA) and micro-computed tomography (micro-CT) . Results: KY-054 concentration-dependently and markedly enhanced ALP activities at 10-9 – 10-5 M maximally up to 4-fold in ST2 cells, indicating that it enhanced osteoblast differentiation. In OVX rats, DEXA showed that KY-054 (3 and 10 mg/kg/day) significantly increased the femur bone mineral density (BMD), and micro-CT showed that it significantly increased the diaphysis bone volume and simulated bone strength parameters without affecting the cancellous bone volume. Furthermore, KY-054 significantly increased bone outer circumference and tended to increase internal circumference, resulting in slight enlargement of the bone marrow cavity. Conclusion: KY-054 has osteogenetic effects on experimental osteoporosis. KY-054 is a potential candidate for osteogenetic drug with unique features for osteoporosis therapy: it increases the cortical but not cancellous bone volume and BMD without causing bone cavity volume reduction.