Drug-induced Physeal Abnormalities in Preclinical Toxicity Studies

Abstract

Most toxic physeal changes are characterized microscopically by altered chondrocyte development, proliferation, or maturation in the growth plate and eventually result in disordered appositional bone growth. Many therapeutic drugs directly or indirectly target proteins involved in chondrocytic differentiation and maturation pathways, so toxic physeal injury has become increasingly common in preclinical toxicologic pathology. While physeal dysplasia has been associated with several different drug classes including bisphosphonates, vascular endothelial growth factor receptor inhibitors, fibroblast growth factor receptor inhibitors, transforming growth factor beta receptor inhibitors, and vascular targeting agents, physeal changes often share similar morphologic features including thickening and disorganization of the hypertrophic layer, increased numbers of hypertrophic chondrocytes, altered mineralization of endochondral ossification, and/or increased thickness of subphyseal bone. Knowledge of genetic and nutritional diseases affecting bone growth has been important in helping to determine which specific target drugs may be affecting that could result in toxic physeal lesions. A pathophysiologic mechanism for most physeal toxicants has been determined in detail using a variety of investigative techniques. However, due to the signaling cross talk and the tight regulation required for chondrocyte maturation in the physis, several growth factor pathways are likely to be affected simultaneously with pharmacologic disruption of physeal homeostasis and inhibition of one factor necessary for chondrocyte function often affects others.

International Harmonization of Nomenclature and Diagnostic Criteria (INHAND): Non-proliferative and Proliferative Lesions of the Non-human Primate (<i>M. fascicularis</i>)

“…Comments: Induced physeal thickening and dysplasia have been associated with several different drug classes 479 . Increased thickness and dysplasia of the physis have been observed in cynomolgus monkeys following treatment with angiogenesis inhibitors, such as an anti-angiogenic humanized monoclonal antibody, rhuMAbVEGF 480 , or a multi-targeted receptor tyrosine kinase (including VEGFR) inhibitor, Sunitinib 481 .…”

Utility of measuring long bone length in toxicity studies: results of a 14-day repeated dose oral toxicity study of dexamethasone in young, periadolescent and adult rats

“…Histopathological evaluation is one of the most commonly used methods to investigate bone toxicity in preclinical general toxicity studies, and histomorphometric and immunohistochemical analyses are occasionally used for additional and special explorations. Measurement of long bone length is an important examination, not only to investigate overall growth in nonclinical safety testing in the development of pediatric medicines (FDA, 2006;ICH, 2018), but also for the detection of drug-induced bone toxicity (Gropp et al, 2018;Frazier, 2017;Vahle et al, 2004). It is easy to compare measured bone lengths, to investigate growth and skeletal abnormalities, by statistical analyses, although measurement of bone length has not been used routinely in general toxicity studies conducted in periadolescent and adult rats, and further information is required to measure the bone length in general toxicity studies conducted in periadolescent and adult rats.…”