Emerging drugs for osteoarthritis

Abstract

Introduction: Osteoarthritis (OA), the most prevalent form of joint disease, affects as much as 13% of the world's population. In the USA, it is the leading cause of disability in people over age 65 and is characterized by progressive cartilage loss, bone remodeling, osteophyte formation and synovial inflammation with resultant joint pain and disability. There are no treatments marketed for structural disease modification; current treatments mainly target symptoms, with > 75% of patients reporting need for additional symptomatic treatment.

Areas covered: Drugs in later development (Phase II - III) for OA pain and joint structural degeneration are reviewed. Topics that are not covered in this article are procedural-based (e.g., arthrocentesis, physical therapy), behavioral-based (e.g., weight loss, pain coping techniques) or device-based (e.g., knee braces, surgical implants) treatments.

Expert opinion: More in-depth understanding of the pathophysiology of the disease, as well as elucidation of the link between clinical symptomatology and structural changes in the joint will likely lead to the development of novel target classes with promising efficacy in the future. Efficacy notwithstanding, there remain significant hurdles to overcome in clinical development of these therapeutics, inherent in the progression pattern of the disease as well as challenges with readouts for both pain and structure modification trials.

Figure 1. Mechanism of nerve growth factor induced hyperalgesia

NGF binds its high affinity receptor TrkA causing phosphorylation and increased activity of TRPv1. NGF undergoes retrograde transport to the dorsal root ganglion, increasing expression of pain signaling factors including substance P, calcitonin gene related peptide(CGRP), TRPV1, brain-derived neurotrophic factor (BDNF) etc., some of which provide central pain perception via release into spinal cord synapses. Increased peripheral hypersensitivity can also be exacerbated by anteriograde transport of TRPV1.