RANKL Inhibition: Preclinical Data

Abstract

Osteoporosis is a complex systemic disease (Pietschmann et al. 2008). Therefore, researchers have to rely on rodent and large animal models for the development of new anti-osteoporotic therapeutics. Rodent models are well established and have been widely used in osteoporosis research. However, the US Food and Drug Administration also demands the use of large animal models besides rats in pre-clinical testing of anti-osteoporotic substances, with an experimental time frame of 12 months when using rats and 16 months when using larger species. According to FDA regulations, valid animal models have to develop an osteoporotic phenotype either spontaneously or after ovariectomy (OVX) (FDA 1994). In order to give an idea of the different biomechanical forces on the skeletons of small vs large animal species, Fig. 1 shows the skeletons of a rat, a sheep, and a miniature pig. There are several ways of inducing osteopenia or osteoporotic phenotypes in mammals, such as OPG gene knock-out, systemic RANKL administration, prolonged glucocorticoid administration, age-related osteoporosis, dietary calcium shortage, OVX, and combinations. All these manipulations have specific advantages and disadvantages. In this chapter, we will focus on rodent and artiodactyl models, but largely spare canine as well as primate models, as these are to be used less frequently due to ethical reasons.