The DMOAD Dream a Generation Later

With the aging of the world’s population, the burden of osteoarthritis (OA) is rising relentlessly, posing enormous costs and challenges to the healthcare system. OA is by far the most common musculoskeletal condition and a major source of chronic pain and disability.¹ The increasing number of patients seeking treatment for OA could very well cause a global financial crisis in the near future. Any hope for avoiding being hit by the storm is fading because few advances in the development of treatments to reduce the progression of the disease have been achieved.

Although some progress has occurred in the symptomatic treatment of the disease, it has been relatively modest, leaving a significant number of patients to live with a painful and crippling disease. Surgery, particularly of weight-bearing joints, has been a useful treatment for end-stage OA.² The need for such an approach is the obvious result of the lack of an otherwise effective medical treatment. The questions to ask at this time are important: What went wrong with the development of therapy in this field of medicine? Why are we faced with such a desperate situation after so much time and effort? Going back in time may help us to understand the situation we are facing today concerning the management and treatment of OA.

Historical Perspective

Decades ago, the burden of OA was much less of a concern from a medical point of view due to the shorter life expectancy of the population. Significant progress in medical care and, more particularly, in the treatment of medical conditions such as cardiovascular diseases and cancer has contributed substantially to increasing life expectancy as well as increasing awareness of the importance of the quality of life. Degenerative diseases linked to aging, such as OA and Alzheimer’s disease, are the aftermath of such a demographic change. This unforeseen increase in the number of patients suffering from these chronic debilitating diseases has resulted in a shortage of effective solutions.

Despite many experimental obstacles, important progress has been made in understanding the pathophysiology of OA. Different biomechanical and biochemical pathophysiological pathways leading to disease development and progression have been identified through major research efforts.^3.4 Moreover, clinical and epidemiological studies and new imaging technology have helped identify important risk factors associated with OA progression and symptoms. For instance, a number of risk factors for disease progression, such as bone marrow lesions, meniscal alterations, and synovitis, have also been associated with OA symptoms.5-8 Interestingly, these latter findings are consistent with those from preclinical research in large animal models, providing support to the results of such investigation.^9,10

An important underlying question in this field relates to the etiopathogenesis of the disease and whether OA is homogeneous in nature. Is the process leading to OA the same from one joint to another, from weight-bearing to non–weight bearing joints, from peripheral to central joints, and between individuals? This query remains largely unanswered and is most relevant in the context of the development of disease-modifying treatments for OA.¹¹ Moreover, the fact that a considerable amount of information available on OA is derived from studies performed on weight-bearing joints may possibly create a bias in the development of new therapies. In that context, the choice of preclinical animal models to study OA should also be carefully examined, ensuring the reproducibility of disease characteristics as in the natural disease.⁹

OA Treatment: From Symptoms to Structural Changes

The knowledge gained from preclinical and clinical research in OA has led to the development of a large number of programs aimed at targeting different disease mechanisms responsible for disease symptoms and structural changes. As mentioned with regard to disease symptoms, a number of local and systemic treatments have been developed that can provide patients with some degree of relief, improving the quality of life.^1,2 However, there remains a high level of unmet needs.¹ Furthermore, some of the treatments, such as nonsteroidal antiinflammatory drugs and narcotics, can cause significant side effects, which are a concern in the aging OA population. Likewise, acetaminophen, the first-line agent recommended by most practice guidelines, has also been demonstrated to have potential toxicity; authorities now recommend its use with caution.¹² The use of symptomatic slow-acting drugs in OA (SySADOA) has become an interesting alternative and has been proven effective, despite criticism.²