Investigation of Bone Toxicity in Drug Development: Review of Current and Emerging Technologies.

Abstract

Assessment and characterization of bone toxicity during drug development is important to ensure the safety of new therapeutics. Drugs can affect bone composition and quality either directly on bone cells or indirectly via systemic effects, leading to alterations in bone density, remodeling and fracture risk. Drug classes known to have harmful effects on bone include antidiabetics, non-steroidal anti-inflammatory drugs (NSAIDs), antivirals, chemotherapeutics, and steroids. Various methods are available to assess and investigate bone toxicity including in vivo animal models, ex vivo organ cultures, and in vitro cell cultures. In addition to routine assessment with in vivo animal models using microscopic examination of bone and clinical pathology parameters (calcium, phosphorus and alkaline phosphatase), other tools such as serum biomarkers of bone turnover, advanced imaging approaches, and histomorphometric analyses provide additional insight into bone microarchitecture and the remodeling process. Emerging in vitro methods, such as microphysiological systems (organ-on-a-chip) technologies, simulating bone's dynamic environment, offer toxicologists useful tools to study drug-induced bone toxicity. In silico models are increasingly recognized as critical tools in assessing drug-induced bone toxicity, offering a complementary approach to traditional in vitro and in vivo methods. Mechanistic models such as pharmacokinetic-pharmacodynamic (PK-PD) frameworks simulate remodeling dynamics and simulate drug metabolism and exposure to explore risk of bone and cartilage toxicity, while finite element models simulate cellular interactions and mechanical stress responses for skeletal toxicity predictions. This review aims to evaluate key features of bone biology impacted by therapeutics with examples and describe techniques for assessing bone toxicity during drug development.