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Review
. 2015 Sep 14;17(1):225.
doi: 10.1186/s13075-015-0747-6.

On the Predictive Utility of Animal Models of Osteoarthritis

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Free PMC article
Review

On the Predictive Utility of Animal Models of Osteoarthritis

Anne-Marie Malfait et al. Arthritis Res Ther. .
Free PMC article

Abstract

Animal models of osteoarthritis are extensively used for investigating disease pathways and for preclinical testing of novel therapies. Their predictive utility, however, has often been questioned, mainly because preclinical efficacy of novel therapeutics is poorly translated in clinical trials. In the current narrative review, we consider the preclinical models that were used to support undertaking clinical trials for disease-modifying osteoarthritis drugs, and compare outcomes between clinical and preclinical studies. We discuss this in light of the 1999 Food and Drug Administration draft guidelines for industry for use in the development of drugs, devices, and biological products intended for the treatment of osteoarthritis, which raised five considerations on the usefulness of osteoarthritis models. We systematically discuss what has been learnt regarding these five points since 1999, with emphasis on replicating distinct risk factors and subtypes of human osteoarthritis, and on comprehensive evaluation of the disease in animals, including pathology of all joint tissues, biomarker analysis, and assessment of pain and joint function. Finally, we discuss lessons learnt and propose some recommendations for how the evidence from preclinical research might be strengthened with a view to improving success in clinical translation.

Figures

Fig. 1
Fig. 1
Osteoarthritis (OA) is a disease of the whole joint with pathology in all articular tissues and associated skeletal muscle. Pain in the OA joint can only arise directly from innervated tissues, but sensory neurons may be activated by factors released from aneural joint tissues
Fig. 2
Fig. 2
Drug development pipeline showing the translational phases (T1 to T4) from basic science discovery through to measurement of impact on population health. Failure of drug development programs can occur at all stages, but the major reasons differ with translational phase. **Efficacy failure is primarily due to poor biological rationale for the clinical trial: target linkage to disease not established or no validated models available (40 %) and indication selected does not fit the strongest preclinical evidence (20 %) [8]. 1[8], 2[142], 3[143], 4[144]

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