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, 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 frameworks, simulate remodeling dynamics and simulate drug metabolism and exposure to explore the risk of bone and cartilage toxicity, whereas 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.

Keywords: biomarkers; complex in vitro models (CIVM); computational modeling; digital pathology; drug development; off target toxicity; skeletal toxicity; toxicity assessment.