Osteoporosis: Mechanism, Molecular Target and Current Status on Drug Development

Abstract

CDATA[Osteoporosis is a pathological loss of bone mass due to an imbalance in bone remodeling where osteoclast-mediated bone resorption exceeds osteoblast-mediated bone formation resulting in skeletal fragility and fractures. Anti-resorptive agents, such as bisphosphonates and SERMs, and anabolic drugs that stimulate bone formation, including PTH analogues and sclerostin inhibitors, are current treatments for osteoporosis. Despite their efficacy, severe side effects and loss of potency may limit the long term usage of a single drug. Sequential and combinational use of current drugs, such as switching from an anabolic to an anti-resorptive agent, may provide an alternative approach. Moreover, there are novel drugs being developed against emerging new targets such as Cathepsin K and 17β-HSD2 that may have less side effects. This review will summarize the molecular mechanisms of osteoporosis, current drugs for osteoporosis treatment, and new drug development strategies.

Keywords: Osteoporosis; anabolic drugs; antiresorptive drugs; bone remodeling; osteoblasts; osteoclasts; osteocytes.

Fig (1).

Therapeutic targets for osteoporosis in bone remodeling. Cell lineage from pre-osteoclast to osteoclast will result in bone resorption and that from pre-osteoblast to osteoblast will result in bone formation. Osteoblast can further differentiate into osteocyte which can regulate both bone resorption and bone formation. RANKL antibodies, estrogen and SERMs, cathepsin K inhibitors, α_vβ₃ integrin inhibitors and bisphosphonates are all considered as antiresorptive drugs, while PTH analogues and sclerostin inhibitors are all considered anabolic drugs, though sclerostin inhibitors work both by inhibiting the functions of osteoclasts and promoting those of osteoblasts.