The disease modifying osteoarthritis drug (DMOAD): Is it in the horizon?

Abstract

Till date, the pharmaceutical industry has failed to bring effective and safe disease modifying osteoarthritic drugs (DMOADs) to the millions of patients suffering from this serious and deliberating disease. We provide a review of recent data reported on the investigation of DMOADs in clinical trials, including compounds inhibiting matrix-metalloproteinases (MMPs), bisphosphonates, cytokine blockers, calcitonin, inhibitors of inducible nitric oxide synthase (iNOS), doxycycline, glucosamine, and diacereine.

We discuss the challenges associated with the drug development process in general and with DMOADs in particular, and we advance the need for a new development paradigm for DMOADs. Two central elements in this paradigm are a stronger focus on the biology of the joint and the application of new and more sensitive biomarkers allowing redesign of clinical trials in osteoarthritis.

Introduction

Osteoarthritis (OA) is one of the leading causes of disability in the world, with more than 10% of the elderly population having symptomatic disease [1]. The incidence increases with age, and by age 65 approximately 80% has radiographic evidence of OA [2]. Therefore, osteoarthritis is a serious burden both to the patient and the society. However, at present there is little to offer the affected individuals for prevention of the disease or treatment in the early stages [3]. For many patients, joint replacement is eventually the only treatment option.

Although the pathogenesis of osteoarthritis is not fully understood at present, it is evident that a central hallmark in this slow, chronic disease is progressive destruction of the articular joints, which consists of bone, cartilage and the synovium. In particular, the cartilage has attracted much attention, and the different grades and stages of OA cartilage histopathology have recently been described in detail by a working group under OARSI [4]. This system encompasses seven grades (or severity levels) with involvement of the deeper cartilage layers in more advanced OA disease, and when combined with the extent of cartilage involvement expressed in five stages this leads to a semi-quantitative scoring system of 0–24. Various skeletal features are included in radiographic assessment of OA [5] and in particular the involvement of subchondral bone remodeling in OA pathogenesis has been reported [6], [7]. The synovium, however, has attracted much less attention.

Current treatment options for OA patients are focused on relief from pain and improvement of joint function, including analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), as well as intra-articular injections of steroids and hyaluronans. Not surprisingly, these medical interventions have little effect – if any at all – on the structural degradation of joint tissue and therefore many patients eventually are faced with surgery as the only option to improve quality of life.

Based on the fact, that a central hallmark in the development of OA is the progressive destruction of the joint tissue, a reasonable approach to the development of an effective medical treatment seems to be the search for drugs with the ability to slow down this process, or maybe even arrest it completely. These drugs, termed disease modifying osteoarthritis drugs (DMOADs), are by nature different from the medical interventions referenced above.

However, a series of disappointing late-stage terminations of clinical trials investigating new potential DMOADs call for careful strategic considerations to improve the drug development process for this type of treatments.

In this review, we provide a brief introduction and perspective to the development of chondroprotective drugs which might be available in the not so distant future. Such treatment options are awaited by millions of patients with osteoarthritis.